Methods for treating pruritus

ABSTRACT

The present invention relates to methods for treating pruritus with anti-pruritic compositions.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 61/737,488, filed Dec. 14, 2012 and U.S. application Ser. No.13/715,625, filed Dec. 14, 2012, all of which are herein incorporated byreference in their entireties.

FIELD OF THE INVENTION

The present invention relates to methods for treating pruritus withanti-pruritic compositions.

BACKGROUND

Pruritus, or itch, is a sensation that stimulates the desire or reflexto scratch, which can be either generalized or localized. The cause ofpruritus is not fully understood. Proposed contributors to thepathogenesis of pruritus may include anemia or other manifestation oferythropoietin deficiency, histamine release from skin mast cells, skindryness, secondary hyperparathyroidism, hyperphosphatemia with increasedcalcium phosphate deposition in the skin and alterations in theendogenous opioidergic system with overexpression of opioid μ-receptors.

SUMMARY OF THE INVENTION

The present invention provides methods for treating various pruriticconditions using nalbuphine or a pharmaceutically acceptable salt orester thereof. In one embodiment, the present invention provides methodsof treating pruritus comprising administering an effective amount of ananti-pruritus agent to a subject in need of such treatment, wherein theanti-pruritus agent is nalbuphine or a pharmaceutically acceptable saltor ester thereof.

In one embodiment, the subject is suffering from a pruritic condition,and said pruritic condition comprises atopic dermatitis, nervousdermatitis, contact dermatitis, seborrheic dermatitis, autosensitizationdermatitis, caterpillar dermatitis, asteatosis, senile prurituscutaneous, insect sting, photosensitive dermatosis, urticaria, prurigo,herpes, impetigo, eczema, tinea, lichen, psoriasis, scabies and acnevulgaris, or visceral diseases complicated with pruritus.

In another embodiment, the subject is suffering from a skin changecomprising pruritus secondary to inflamed skin, pruritus arising fromconditions of non-diseased skin, pruritus associated with chronicsecondary scratch, or skin lesions resulting from an underlying medicalcondition.

In yet another embodiment, the subject has uremic pruritus or prurigonodularis.

In some embodiments, the anti-pruritus agent is administered at aninitial oral dose of from about 15 mg to about 30 mg once or twice a dayand then titrated to an effective dose.

In some other embodiments, the anti-pruritus agent is administered at aninitial dose of from about 15 mg to about 30 mg twice a day or once aday for about 2-3 days and then titrated to an effective dose at about15 mg to about 30 mg increment.

In yet some other embodiments, the maximum dose of the anti-pruritusagent is about 480 mg when said agent is administered to a subject twicea day or about 240 mg when said agent is administered to a subject oncea day.

In some embodiments, the anti-pruritus agent is administered with an AMdosage and a PM dosage and wherein the PM dosage is higher than the AMdosage, or vice versa.

In some other embodiments, the anti-pruritus agent is administered at adose of about 60 mg or about 120 mg twice a day to a subject with uremicpruritus or renal impairment or about 90 mg or about 180 mg twice a dayto a subject without a renal impairment condition.

In some embodiments, the anti-pruritus agent is in an extended releaseoral dosage form and the administration provides in the subject a meanC_(max) of from about 1 ng/mL to about 90 ng/mL, from about 5 ng/mL toabout 85 ng/mL, from about 5 ng/ml to about 45 ng/ml, from about 25ng/mL to about 72 ng/mL, or from about 13 ng/mL to about 28 ng/mL.

In some other embodiments, the anti-pruritus agent is in an extendedrelease oral dosage form and the administration provides in the subjectan AUC_((0-∞)) of from about 40 ng·hr/mL to about 3000 ng·hr/mL, 40ng·hr/mL to about 800 ng·hr/mL or 30 ng·hr/mL to about 360 ng·hr/mL.

In some embodiments, the anti-pruritus agent is in an extended releaseoral dosage form.

In some other embodiments, the administration provides in the subject apK release profile with the characteristics of a) a mean C_(max) fromabout 1.5 ng/mL to about 195 ng/mL, and b) AUC_((0-∞)) from about 20ng·hr/mL to about 4100 ng·hr/mL.

In yet some other embodiments, the administration provides in thesubject a pK release profile with the characteristics of a) a meanC_(max) from about 1.5 ng/mL to about 60 ng/mL, and b) AUC_((0-∞)) fromabout 20 ng·hr/mL to about 700 ng·hr/mL.

The present methods, and advantages thereof, are further illustrated bythe following non-limiting detailed description and Examples.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of the log of the mean nalbuphineplasma concentration versus time for several nalbuphine compositions.

DETAILED DESCRIPTION

The word “about” when immediately preceding a numerical value means arange of plus or minus 10% of that value, e.g., “about 50” means 45 to55, “about 25,000” means 22,500 to 27,500, etc., unless the context ofthe disclosure indicates otherwise, or is inconsistent with such aninterpretation. For example in a list of numerical values such as “about49, about 50, about 55, . . . ”, “about 50” means a range extending toless than half the interval(s) between the preceding and subsequentvalues, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases“less than about” a value or “greater than about” a value should beunderstood in view of the definition of the term “about” providedherein.

Throughout this disclosure, various patents, patent applications andpublications are referenced. The disclosures of these patents, patentapplications and publications in their entireties are incorporated intothis disclosure by reference in order to more fully describe the stateof the art as known to those skilled therein as of the date of thisdisclosure. This disclosure will govern in the instance that there isany inconsistency between the patents, patent applications andpublications cited and this disclosure.

For convenience, certain terms employed in the specification, examplesand claims are collected here. Unless defined otherwise, all technicaland scientific terms used in this disclosure have the same meanings ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs.

The term “salts” as used herein embraces pharmaceutically acceptablesalts commonly used to form alkali metal salts of free acids and to formaddition salts of free bases. The nature of the salt is not critical,provided that it is pharmaceutically acceptable. The term “salts” alsoincludes solvates of addition salts, such as hydrates, as well aspolymorphs of addition salts. Suitable pharmaceutically acceptable acidaddition salts can be prepared from an inorganic acid or from an organicacid. Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Appropriateorganic acids can be selected from aliphatic, cycloaliphatic, aromatic,arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonicacids, for example formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic,stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,cyclohexylaminosulfonic, algenic, 3-hydroxybutyric, galactaric andgalacturonic acid.

The terms “administer,” “administering” or “administration” as usedherein refer to either directly administering a compound orpharmaceutically acceptable salt of the compound or a composition to asubject.

The term “carrier” as used herein encompasses carriers, excipients, anddiluents, meaning a material, composition or vehicle, such as a liquidor solid filler, diluent, excipient, solvent or encapsulating materialinvolved in carrying or transporting a pharmaceutical agent from oneorgan, or portion of the body, to another organ or portion of the body.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The terms “effective amount” and “therapeutically effective amount” areused interchangeably in this disclosure and refer to an amount of acompound that, when administered to a subject, is capable of reducing asymptom of a disorder in a subject. The actual amount which comprisesthe “effective amount” or “therapeutically effective amount” will varydepending on a number of conditions including, but not limited to, theseverity of the disorder, the size and health of the patient, and theroute of administration. A skilled medical practitioner can readilydetermine the appropriate amount using methods known in the medicalarts.

The phrase “pharmaceutically acceptable” as used herein refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used in this disclosure, the term “subject” includes, withoutlimitation, a human or an animal. Exemplary animals include, but are notlimited to, mammals such as mouse, rat, guinea pig, dog, cat, horse,cow, pig, monkey, chimpanzee, baboon, or rhesus monkey.

The term “treating” as used herein with regard to a subject, refers toimproving at least one symptom of the subject's disorder. Treating canbe curing, improving, or at least partially ameliorating a disorder.

Nalbuphine

Nalbuphine HCl (17-(cyclobutylmethyl)-4,5α-epoxymorphinian-3, 6α,14-triol, hydrochloride) is currently available only as a genericmedication in an injectable form. An injectable form of nalbuphine hasbeen available as an approved drug formulation since 1978. Nubain® wasthe innovator brand injectable form of nalbuphine on which the presentlysold generic bioequivalent injectable formulations are based. Theinjectable formulation is currently approved for use in the relief ofmoderate to severe pain, a supplement to balanced anesthesia, forpre-operative and post-operative analgesia and obstetrical analgesiaduring labor and delivery.

Opioid Receptors

There are three classical types of opioid receptors that have beeninvestigated as the mediators of opiate effects. These opioid receptorsare classified as mu (“μ”), kappa (“κ”) and delta (“δ”). Nalbuphine is aderivative of 14-hydroxymorphine and is structurally related to theopioid μ-receptor agonist oxymorphone and the opioid μ-receptorantagonist naloxone. Gutstein et al. (Chapter 23: Opioid Analgesics,Goodman & Gilman's The Pharmacologic Basis of Therapeutics, 10th Ed.,McGraw Hill 2001, pp 569-619) report that nalbuphine exerts its clinicalpharmacologic action by competitively antagonizing the opioid μ-receptorand simultaneously acting as an agonist at the opioid κ-receptor, andthus is a member of the “opioid agonist-antagonist” class of drugs thatmechanistically work through this dual pharmacologic process. Subsequentin vitro work by Gharagozlou et al. (Neurosci. 2002 3:19) showed thatnalbuphine is in addition a 6 opioid receptor antagonist. Gutstein etal. (supra) state that the stimulus for the development opioidagonist-antagonist drugs was to identify a drug with analgesicproperties with less respiratory depression and addiction potential.

Nalbuphine in the Treatment of Pruritus

In a first aspect, the present invention provides a method of treatingpruritus comprising administering an effective amount of ananti-pruritus agent to a subject in need of such treatment, wherein theanti-pruritus agent is nalbuphine or a pharmaceutically acceptable saltor ester thereof.

“Nalbuphine” includes nalbuphine free base, metabolites thereof,derivatives thereof, solvates thereof (e.g., hydrates, alcoholates,etc.) and/or pharmaceutically acceptable salts or esters thereof.Metabolites of nalbuphine include, for example the glucuronide conjugatemetabolite and metabolites resulting from methylation,oxidation/dehydrogenation, hydroxylation, double hydroxylation, triplehydroxylation, oxidative methylation, glucoside conjugation, glucuronideconjugation, and hydroxyl-glucuronide conjugation of nalbuphine.Exemplary metabolites can include nornalbuphine, 6-ketonalbuphine,nalbuphine 3-glucuronide. In one embodiment, metabolites include triplehydroxylated nalbuphine, mono-hydroxylated nalbuphine, andmono-glucuronidated nalbuphine. Isomers include the C-6β-epimer ofnalbuphine (Mallinckrodt, Nalbuphine hydrochloride Technical PackageAugust 2003). Derivatives of nalbuphine can include pharmaceuticallyacceptable ester prodrugs thereof (including alkoxy esters such asmethoxy and ethoxy esters) which can be hydrolyzed in vivo to providenalbuphine, as well as ether or other compounds prepared by, e.g.reacting the hydroxyl groups of nalbuphine with suitable protectingagents.

In one embodiment, nalbuphine suitable for use in the present methods isin the form of any pharmaceutically acceptable salt or ester known inthe art. Exemplary pharmaceutically acceptable salts include withoutlimitation hydrochloric, sulfuric, nitric, phosphoric, hydrobromic,maleic, malic, ascorbic, citric, tartaric, pamoic, lauric, stearic,palmitic, oleic, myristic, lauryl sulfuric, napthalinesulfonic,linoleic, linolenic acid, and the like. In one embodiment theanti-pruritus agent is the hydrochloride salt of nalbuphine.

The present invention also includes pharmaceutically acceptable estersof the anti-pruritic agent. The term “ester” denotes a derivative of theanti-pruritic agent containing an ester functional group (as describedherein), which is capable of releasing the anti-pruritic agent when theester form is administered to a subject. Release of the activeingredient occurs in vivo. Pharmaceutically acceptable esters can beprepared by techniques known to one skilled in the art. These techniquesgenerally modify appropriate functional groups in a given compound.These modified functional groups however regenerate original functionalgroups by metabolism of the compound in vivo. Esters include compoundswherein a hydroxy, amino, carboxylic, or a similar group is modified.

Suitable pharmaceutically acceptable esters for a hydroxyl group includeinorganic esters such as phosphate esters and α-acyloxyalkyl ethers andrelated compounds which, as a result of in vivo hydrolysis of the ester,provide the parent hydroxy group. In vivo hydrolyzable ester forminggroups for hydroxy include alkanoyl (e.g., C₁₋₁₀ linear, branched orcyclic alkyl), benzoyl, phenylacetyl and substituted benzoyl andphenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters),dialkylcarbamoyl and N—(N,N-dialkylaminoethyl)-N-alkylcarbamoyl (to givecarbamates), N,N-dialkylaminoacetyl and carboxy acetyl.

Nalbuphine as employed in the present methods can form a part of apharmaceutical composition by combining nalbuphine, or apharmaceutically acceptable salt or ester thereof, with apharmaceutically acceptable carrier. Additionally, the compositions caninclude an additive selected from the group consisting of adjuvants,excipients, diluents, release-modifying agents and stabilizers. Thecomposition can be an immediate release formulation, a delayed releaseformulation, a sustained release formulation or an extended releaseformulation.

Pruritic Conditions

According to the present invention, pruritus includes any itchy orpruritic condition, e.g., a sensation that causes the desire or reflexto scratch. In some embodiments, methods of the present invention areused for the treatment of a subject suffering from a pruritic conditionselected from the group consisting of atopic dermatitis, nervousdermatitis, contact dermatitis, seborrheic dermatitis, autosensitizationdermatitis, caterpillar dermatitis, asteatosis, senile prurituscutaneous, insect sting, photosensitive dermatosis, urticarial, prurigo,herpes, impetigo, eczema, tinea, lichen, psoriasis, scabies and acnevulgaris, visceral diseases complicated with pruritus such as malignanttumors, diabetes mellitus, hepatic diseases, renal failure,hemodialysis, peritoneal dialysis, and pregnancy.

In some embodiments, methods of the present invention are used for thetreatment of a subject suffering from a pruritic condition associatedwith a skin change. For example, such pruritic condition can be selectedfrom the group consisting of pruritus secondary to inflamed skin (e.g.,atopic dermatitis, psoriasis, burns); pruritus arising from conditionsof non-diseased skin (e.g., uremic pruritus, cholestatic pruritus,cancers, hydroxyethyl starch induced pruritus), and pruritus associatedwith chronic secondary scratch or other types of skin lesions that mayor may not be the result of an underlying medical condition (e.g.,prurigo nodularis) and the underlying disease is categorized based onhistological, radiological or other investigations as being of an originselected from the group consisting of dermatologic origin, systemicdisease origin, neurologic origin, psychogenic origin, mixed origin, orother origin.

In some embodiments, methods of the present invention are used for thetreatment of a subject suffering from a pruritic condition associatedwith neurogenic inflammation of the skin, e.g., prurigo nodularis,atopic dermatitis, burn pruritus, burn, wound healing, etc. In someother embodiments, methods of the present invention are used for thetreatment of a subject suffering from a pruritic condition associatedwith neurogenic inflammation with elevated substance P level. In stillsome other embodiments, methods of the present invention are used forthe treatment of a subject suffering from a pruritic conditionassociated with elevated substance P level.

In some embodiments, methods of the present invention are used for thetreatment of a subject suffering from a pruritic condition associatedwith one or more related or unrelated conditions. For example, thepruritic condition can be associated with a dermatologic conditionincluding aquagenic pruritus, atopic dermatitis, idiopathic pruritus,Lichen simplex chronicus, prurigo nodularis, psoriasis, and scabies. Inanother example, the pruritic condition can be associated with ahematological or oncological condition including cancer relatedpruritus, chemotherapy induced pruritus, HIV protease inhibitor inducedpruritus, Hodgkin's lymphoma associated pruritus, polycythemia vera,etc. In another example, the pruritic condition can be associated with ametabolic condition including cholestatic pruritus, uremic pruritus,etc. In still another example, the pruritic condition can be associatedwith a condition of pain or neurological condition includingbrachioradial pruritus, burn induced pruritus, neuropathic pruritus,morphine induced pruritus, multiple sclerosis associated pruritus, postherpetic pruritus, pruritus associated with psychiatric causes, etc.

In one embodiment, methods of the present invention are used for thetreatment of uremic pruritus. In another embodiment, methods of thepresent invention are used for the treatment of prurigo nodularis. Inyet another embodiment, methods of the present invention are used totreat human beings. In still another embodiment, methods of the presentinvention are used to treat animals other than human beings.

Formulations

The methods of the present invention can employ various formulations foradministration to subjects, e.g., humans and animals in unit dosageforms, such as tablets, capsules, pills, powders, granules, sterileparenteral solutions or suspensions, and oral solutions or suspensions,and oil-water emulsions containing suitable quantities of ananti-pruritic agent, e.g., nalbuphine, or pharmaceutically acceptablesalts or esters thereof.

Oral pharmaceutical dosage forms can be either solid or liquid. Thesolid dosage forms can be tablets, capsules, granules, and bulk powders.Types of oral tablets include compressed, chewable lozenges and tabletswhich can be enteric-coated, sugar-coated or film-coated. Capsules canbe hard or soft gelatin capsules, while granules and powders can beprovided in non-effervescent or effervescent form with the combinationof other ingredients known to those skilled in the art. In otherembodiments, the oral dosage form may be an osmotic-controlled releaseoral delivery system (OROS). In other embodiments, the oral dosage formmay include matrix-embedded dosage forms or related devices. In someembodiments, the present oral dosage forms may includeorally-disintegrating tablets.

Pharmaceutically acceptable carriers utilized in tablets includebinders, lubricants, diluents, disintegrating agents, coloring agents,flavoring agents, and wetting agents.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules.

Aqueous solutions include, for example, elixirs and syrups. Emulsionscan be either oil-in water or water-in-oil. Elixirs are clear,sweetened, hydroalcoholic preparations. Pharmaceutically acceptablecarriers used in elixirs include solvents. Syrups can be concentratedaqueous solutions of a sugar, for example, sucrose, and can contain apreservative. An emulsion is a two-phase system in which one liquid isdispersed in the form of small globules throughout another liquid.Pharmaceutically acceptable carriers used in emulsions are non-aqueousliquids, emulsifying agents and preservatives. Suspensions can usepharmaceutically acceptable suspending agents and preservatives.Pharmaceutically acceptable substances used in non-effervescentgranules, to be reconstituted into a liquid oral dosage form, includediluents, sweeteners and wetting agents. Pharmaceutically acceptablesubstance used in effervescent granules, to be reconstituted into aliquid oral dosage form, can include organic acids and a source ofcarbon dioxide. Coloring and flavoring agents can be used in all of theabove dosage forms.

Parenteral administration of the formulations of the present inventionincludes intravenous, subcutaneous and intramuscular administrations. ofimmediate, sustained (e.g., depot), extended, and/or modified releaseformulations (e.g., as described herein). Preparations for parenteraladministration include sterile solutions ready for injection, steriledry soluble products ready to be combined with a solvent just prior touse, including hypodermic tablets, sterile suspensions ready forinjection, sterile dry insoluble products ready to be combined with avehicle just prior to use and sterile emulsions. The solutions can beeither aqueous or nonaqueous. Pharmaceutically acceptable carriers usedin parenteral preparations include aqueous vehicles, nonaqueousvehicles, antimicrobial agents, isotonic agents, buffers, antioxidants,local anesthetics, suspending and dispersing agents, emulsifying agents,sequestering or chelating agents and other pharmaceutically acceptablesubstances.

The concentration of the pharmaceutically active compound can beadjusted so that an injection provides an effective amount to producethe desired pharmacological effect. The exact dose depends on the age,weight and condition of the patient or animal, as is known in the art.The unit-dose parenteral preparations are packaged in an ampoule or asyringe with a needle. All preparations for parenteral administrationmust be sterile, as is known and practiced in the art. Illustratively,intravenous or intra-arterial infusion of a sterile aqueous solutioncontaining an anti-pruritic agent is an effective mode ofadministration.

Pharmaceutical dosage forms for rectal administration can be rectalsuppositories, capsules and tablets for systemic effect. Rectalsuppositories as used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing thepharmacologically and/or therapeutically active ingredients contained inthe composition of this invention. Pharmaceutically acceptablesubstances utilized in rectal suppositories are bases or vehicles andagents to raise the melting point. Examples of bases include cocoabutter (theobroma oil), glycerin-gelatin, carbowax, polyoxyethyleneglycol and mixtures of mono-, di- and triglycerides of fatty acids.Combinations of the various bases can be used. Agents to raise themelting point of suppositories include spermaceti and wax. Rectalsuppositories can be prepared either by the compressed method or bymolding. The typical weight of a rectal suppository is about 2 to 3 gm.Tablets and capsules for rectal administration can be manufactured usingthe same pharmaceutically acceptable substance and by the same methodsas for formulations for oral administration.

The compositions can be suspended in micronized or other suitable formor can be derivatized to produce a more soluble active product. The formof the resulting composition depends upon a number of factors, includingthe intended mode of administration and the solubility of theanti-pruritic agent in the selected carrier or vehicle. The effectiveconcentration is sufficient for treating or alleviating pruritus, andcan be empirically determined. The concentration is generally greaterthan the concentration for systemic administration of the compound.

The resulting mixture can be a solution, suspension, emulsion or thelike, and can be formulated as a cream, gel, ointment, emulsion,solution, elixir, lotion, suspension, tincture, paste, foam, aerosol,irrigation, spray, suppository, bandage, or any other formulationsuitable for topical or local administration. Modes of administrationcan include topical application to the skin, scalp, eyes, and/or nasal,buccal or sublingual mucosa.

Pharmaceutical and cosmetic carriers or vehicles suitable foradministration of the compositions include any such carriers known tothose skilled in the art to be suitable for the particular mode ofadministration. The anti-pruritic agent can be included in the carriersin amounts sufficient to exert a therapeutically useful effect withoutserious toxic effects on the treated individual.

To formulate these compositions, a weight fraction of an anti-pruriticagent is dissolved, suspended, dispersed or otherwise mixed in aselected vehicle at an effective concentration such that the pruriticcondition is relieved or ameliorated. Generally, emollient orlubricating vehicles that help hydrate the skin are more preferred thanvolatile vehicles, such as ethanol, that dry the skin. Examples ofsuitable bases or vehicles for preparing compositions for use with humanskin are petrolatum, petrolatum plus volatile silicones, lanolin, coldcream (USP), and hydrophilic ointment (USP).

The compositions employed in the present methods can relieve prurituswhen applied to the skin. The composition can be administered topicallyto the affected area up to eight times per day, as needed, to providereduction in and relief from itching. Relief can be temporary orpermanent, and can even be evident after a single dose of thecomposition. When the composition is administered in a form other than atopical preparation, it should be administered in an amount sufficientto provide relief from pruritus that is within safety guidelinesestablished by the FDA. Determining the appropriate amount to administerto a patient is within the skill of the person of ordinary skill in theart in association with teachings provided by the present invention.

Solutions of the compositions of this invention intended for topicaladministration contain an amount of the composition effective to deliveran anti-pruritic amount, typically at a concentration of between about0.01% w/w to about 5% w/w. The balance of the solution is water, asuitable organic solvent or other suitable solvent or buffer. Thesecompositions that are formulated as solutions or suspensions can beapplied to the skin, or can be formulated as an aerosol or foam andapplied to the skin as a spray-on. The aerosol compositions typicallycontain from 25% to 80% w/w, preferably from 30% to 50% w/w, of asuitable propellant. Gel compositions can be formulated by simplyadmixing a suitable thickening agent to the solution or suspension.

Solutions and suspensions can also be topically applied to the eyes andmucosa. Solutions, particularly those intended for ophthalmic use, canbe formulated as 0.01%-10% w/w isotonic solutions, pH about 5-7, withappropriate salts, and preferably containing one or more of thecompositions herein at a concentration of about 0.1% w/w, up to about 5%w/w or more. Suitable ophthalmic solutions are known in the art.

Compositions of solid forms intended for topical application can beformulated as stick-type compositions intended for application to thelips or other parts of the body. Such compositions contain an effectiveamount of an anti-pruritic agent, e.g. nalbuphine or a pharmaceuticallyacceptable salt or ester thereof. The amount of the anti-pruritic agentpresent is typically from about 0.01% w/w to about 5% w/w. The solidsalso contain from about 40% to 98% w/w, preferably from about 50% to 90%w/w, of emollients. This composition can further contain from 1% to 20%w/w, preferably from 5% to 15% w/w, of a suitable thickening agent, and,if desired or needed, emulsifiers and water or buffers.

In addition, the compositions, and preparations containing thecompositions, can also be coated on bandages, mixed with bioadhesives,or included in dressings. Thus, combinations of bandages, bioadhesives,dressings and other such materials and the compositions formulated asdescribed herein are provided.

Sustained Release Formulations

Nalbuphine formulations which can be employed in the present methodsinclude oral sustained release nalbuphine formulations as described inU.S. Provisional Pat. Appl. Nos. 60/772,466 and 60/710,772; and U.S.patent application Ser. Nos. 11/509,347 and 12/154,496 (published asU.S. Patent Publications 2007/0048376 and 2009/0030026, respectively),each of which is incorporated herein by reference in their entireties.

In some embodiments, the present methods can employ oral sustainedrelease formulations of nalbuphine including an anti-pruritic effectiveamount of nalbuphine or a pharmaceutically acceptable salt or esterthereof. The oral sustained release formulations can provide acontrolled release of the drug over a longer period than observed forbolus injections or immediate release oral formulations (e.g., at leastabout 8-12 hours). Reducing the frequency of dosing provides thepotential for enhanced patient convenience and compliance with thepresent methods. The lower dosing frequency also has the potential toprovide reduced side effects because the patient may be exposed to lowerpeak concentrations of drug over time.

The present methods can employ compositions including nalbuphine or apharmaceutically acceptable salt or ester thereof and a sustainedrelease delivery system. The sustained release delivery system includes(i) at least one hydrophilic compound, at least one cross-linking agent,and at least one pharmaceutical diluent; (ii) at least one hydrophiliccompound, at least one cross-linking agent, at least one pharmaceuticaldiluent, and at least one cationic cross-linking agent different fromthe first cross-linking agent; or (iii) at least one hydrophiliccompound, at least one cationic cross-linking compound, and at least onepharmaceutical diluent. Alternatively, in other embodiments, the presentmethods can employ compositions including nalbuphine or apharmaceutically acceptable salt or ester thereof and a sustainedrelease delivery system, which may employ a hydrophobic compound in asustained release system.

The nalbuphine can be homogeneously dispersed in the sustained releasedelivery system. In some embodiments, the nalbuphine or pharmaceuticallyacceptable salt or ester thereof is present in the composition in anamount of about 1 mg to about 240 mg; about 1 mg to about 150 mg; about1 mg to about 125 mg; or about 1 mg to about 100 mg. In someembodiments, the nalbuphine or pharmaceutically acceptable salt or esterthereof is present in the composition in an amount of about 5 mg toabout 80 mg; about 10 mg to about 70 mg; about 15 mg to about 60 mg;about 40 mg to about 80 mg; about 50 mg to about 70 mg; or about 45 mgto about 60 mg. In one embodiment, the nalbuphine or pharmaceuticallyacceptable salt or ester thereof is present in the composition in anamount of about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg,about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190mg, or about 240 mg. In another embodiment, the nalbuphine orpharmaceutically acceptable salt thereof is present in the compositionin an amount of about 30 mg, about 45 mg, about 60 mg, about 120 mg, orabout 180 mg. In yet another embodiment, the nalbuphine orpharmaceutically acceptable salt thereof is present in the compositionin an amount of about 15 mg, 30 mg, 90 mg, 120 mg or 180 mg.

In yet another embodiment, the nalbuphine or pharmaceutically acceptablesalt thereof, e.g., HCL is present in the composition in an amount ofabout 15 mg, about 30 mg, about 90 mg, about 120 mg, or about 180 mg.

In some embodiments, the sustained release delivery system is present inthe composition in an amount from about 10 mg to about 420 mg; fromabout 25 mg to about 225 mg; from about 21 mg to about 198 mg; or fromabout 80 mg to about 200 mg; from about 80 mg to about 220 mg; fromabout 90 mg to about 210 mg; from about 100 mg to about 200 mg; fromabout 110 mg to about 190 mg; from about 120 mg to about 180 mg; fromabout 130 mg to about 170 mg; from about 140 mg to about 160 mg; fromabout 30 mg to about 60 mg; from about 60 mg to about 180 mg; from about30 mg to about 180 mg, from about 75 mg to about 150 mg, from about 80mg to about 160 mg, from about 90 mg to about 150 mg, from about 100 mgto about 140 mg, from about 110 mg to about 130 mg, from about 100 mg toabout 300 mg, from about 200 mg to about 300 mg or from about 200 mg toabout 250 mg. In one embodiment, the sustained release delivery systemis present in the composition in an amount from about 75 mg to about 150mg.

In some embodiments, the sustained release delivery system is present inthe composition in an amount of about 30 mg, about 60 mg, about 75 mg,about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 112 mg,about 115 mg, about 117 mg, about 120 mg, about 125 mg, about 130 mg,about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 160 mg,about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg,about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg,about 260 mg, about 270 mg, about 280 mg, about 300 mg, about 320 mg,about 340 mg, about 360 mg, about 380 mg, about 400 mg or about 420 mg.In another embodiment, the sustained release delivery system is presentin the composition in an amount of about 112 mg.

The ratio of nalbuphine or pharmaceutically acceptable salt or esterthereof in the compositions to the sustained release delivery system isgenerally from about 4:1 to about 1:25. In some embodiments, the ratioof nalbuphine or pharmaceutically acceptable salt or ester thereof tothe sustained release delivery system is generally from about 2.5:1 toabout 1:4. In some embodiments, the ratio of nalbuphine orpharmaceutically acceptable salt or ester thereof to the sustainedrelease delivery system is generally from about 5:1 to about 1:5, about4:1 to about 1:4, about 3:1 to about 1:3, about 2:1 to about 1:2, about1:1 to about 1:5, about 1:1 to about 1:4, about 1:1 to about 1:3, about1:1 to about 1.2, and about 1:2 to about 1:3. In some embodiments, theratio of nalbuphine or pharmaceutically acceptable salt or ester thereofto the sustained release delivery system is about 1:1, about 1:2, about1:2.5, about 1:3, about 1:4, or about 1:5.

In one embodiment, at least one hydrophilic compound is present in thesustained release delivery system in an amount of about 5% to about 80%by weight; the at least one cross-linking agent is present in thesustained release delivery system in an amount of about 0.5% to about80% by weight; and the at least one pharmaceutical diluent is present inthe sustained release delivery system in an amount of about 20% to about80% by weight. In another embodiment, the at least one hydrophiliccompound is present in the sustained release delivery system in anamount of about 8% to about 31% by weight; the at least onecross-linking agent is present in the sustained release delivery systemin an amount of about 12% to about 47% by weight; and the at least onepharmaceutical diluent is present in the sustained release deliverysystem in an amount of about 20% to about 78% by weight. In anotherembodiment, the at least one hydrophilic compound is present in thesustained release delivery system in an amount of about 10% to about 20%by weight; the at least one cross-linking agent is present in thesustained release delivery system in an amount of about 15% to about 25%by weight; and the at least one pharmaceutical diluent is present in thesustained release delivery system in an amount of about 50% to about 85%by weight. In some embodiments, the at least one hydrophilic compound ispresent in the sustained release delivery system in an amount of about8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%,about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about22%, about 24%, about 26%, about 28%, about 30%, about 32%, about 34%,or about 36% by weight; the at least one cross-linking agent is presentin the sustained release delivery system in an amount of about 10%,about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about17%, about 18%, about 19%, about 20%, about 22%, about 24%, about 26%,about 28%, about 30%, about 32%, about 33%, about 34%, or about 35% byweight; and the at least one pharmaceutical diluent is present in thesustained release delivery system in an amount of about 40%, about 45%,about 50%, about 55%, about 60%, about 65%, about 70%, about 80%, orabout 85% by weight.

In some embodiments, the at least one hydrophilic compound is present inthe sustained release delivery system in an amount of about 10%, about11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%,about 18%, about 19%, or about 20% by weight; the at least onecross-linking agent is present in the sustained release delivery systemin an amount of about 15%, about 16%, about 17%, about 18%, about 19%,about 20%, or about 22% by weight; and the at least one pharmaceuticaldiluent is present in the sustained release delivery system in an amountof about 55%, about 60%, about 65%, about 70%, about 80%, or about 85%by weight. In one embodiment, the at least one hydrophilic compound ispresent in the sustained release delivery system in an amount of about8%, about 12%, or about 20% by weight; the at least one cross-linkingagent is present in the sustained release delivery system in an amountof about 12%, about 18%, or about 30% by weight; and the at least onepharmaceutical diluent is present in the sustained release deliverysystem in an amount of about 40%, about 60%, or about 70% by weight.

In one embodiment, nalbuphine is in the form of any pharmaceuticallyacceptable salt known in the art. Exemplary pharmaceutically acceptablesalts include without limitation hydrochloric, sulfuric, nitric,phosphoric, hydrobromic, maleric, malic, ascorbic, citric, tartaric,pamoic, lauric, stearic, palmitic, oleic, myristic, lauryl sulfuric,napthalinesulfonic, linoleic, linolenic acid, and the like. Oneembodiment includes the hydrochloride salt of nalbuphine.

The sustained release delivery system includes at least one hydrophiliccompound. The hydrophilic compound preferably forms a gel matrix thatreleases the nalbuphine or the pharmaceutically acceptable salt or esterthereof at a sustained rate upon exposure to liquids. The rate ofrelease of the nalbuphine or the pharmaceutically acceptable salt orester thereof from the gel matrix depends on the drug's partitioncoefficient between the components of the gel matrix and the aqueousphase within the gastrointestinal tract. The weight ratio of nalbuphineto hydrophilic compound is generally in the range of about 10:1 to about1:10, about 9:1 to about 1:9, about 8:1 to about 1:8, about 7:1 to about1:7, about 6:1 to about 1:6, about 5:1 to about 1:5, about 4:1 to about1:4, about 3:1 to about 1:3, and about 2:1 to about 1:2. In someembodiments, the weight ratio of nalbuphine to hydrophilic compound isin the range of about 10:1 to about 1:1, about 10:1 to about 2:1, about9:1 to about 1:1, about 8:1 to about 1:1, about 7:1 to about 1:1, about6:1 to about 1:1, about 5:1 to about 1:1, about 4:1 to about 1:1, about3:1 to about 1:1, and about 2:1 to about 1:1. In some embodiments, theweight ratio of nalbuphine to hydrophilic compound is in the range ofabout 6:1 to about 1:1, about 5:1 to about 2:1, about 4:1 to about 3:1,about 4:1 to about 2:1, and about 5:1 to about 2:1. In some embodiments,the weight ratio of nalbuphine to hydrophilic compound is about 1:5,about 1:4.5, about 1:4.4, about 1:4, about 1:3.5, about 1:3.3, about1:3, about 1:2.5, about 1:2, about 1:1, and about 1:1.5.

The sustained release delivery system generally includes the hydrophiliccompound in an amount of about 5% to about 80% by weight. In someembodiments, the sustained release delivery system generally includesthe hydrophilic compound in an amount of about 5% to about 30%, about 8%to about 31%, about 10% to about 20%, about 20% to about 60%, or about40% to about 60% by weight. In one embodiment, the sustained releasedelivery system includes the hydrophilic compound in an amount of about8% to about 31% by weight. In one embodiment, the sustained releasedelivery system includes the hydrophilic compound in an amount of about10% to about 20% by weight. In some embodiments, the sustained releasedelivery system includes the hydrophilic compound in an amount of about10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%,about 17%, about 18%, about 19%, or about 20% by weight. In oneembodiment, the sustained release delivery system includes thehydrophilic compound in an amount of about 12% by weight. In oneembodiment, the sustained release delivery system includes thehydrophilic compound in an amount of about 8% by weight. In oneembodiment, the sustained release delivery system includes thehydrophilic compound in an amount of about 20% by weight. In oneembodiment, the sustained release delivery system includes thehydrophilic compound in an amount of about 28% by weight.

The hydrophilic compound is any compound known in the art to behydrophilic. Exemplary hydrophilic compounds include without limitationgums, cellulose ethers, polyvinyl pyrrolidone, protein-derivedcompounds, and mixtures thereof. Exemplary gums include withoutlimitation heteropolysaccharide gums and homopolysaccharide gums, suchas xanthan, tragacanth, pectins, acacia, karaya, alginates, agar, guar,hydroxypropyl guar, carrageenan, locust bean gums, and gellan gums.Exemplary cellulose ethers include without limitation hydroxyalkylcelluloses and carboxyalkyl celluloses. In some embodiments, celluloseethers include hydroxyethyl celluloses, hydroxypropyl celluloses,hydroxypropylmethyl-celluloses, carboxy methylcelluloses, and mixturesthereof. In some embodiments, the hydrophilic compound is a gum. Inother embodiments, the hydrophilic compound is a heteropolysaccharidegum. In further embodiments, the hydrophilic compound is a xanthan gumor derivative thereof. Derivatives of xanthan gum include withoutlimitation, for example, deacylated xanthan gum, the carboxymethylesters of xanthan gum, and the propylene glycol esters of xanthan gum.

In another aspect, the sustained release delivery system furtherincludes at least one cross-linking agent. In one embodiment, thecross-linking agent is a compound that is capable of cross-linking thehydrophilic compound to form a gel matrix in the presence of liquids. Asused herein, “liquids” includes, for example, gastrointestinal fluidsand aqueous solutions, such as those used for in vitro dissolutiontesting. The sustained release delivery system generally includes thecross-linking agent in an amount of about 0.5% to about 80% by weight.In one embodiment, the sustained release delivery system generallyincludes the cross-linking agent in an amount of about 12% to about 47%by weight. In another embodiment, the sustained release delivery systemgenerally includes the cross-linking agent in an amount of about 20% toabout 30% by weight. In one embodiment, the sustained release deliverysystem generally includes the cross-linking agent in an amount of about15% to about 25% by weight. In some embodiments, the at least onecross-linking agent is present in the sustained release delivery systemin an amount of about 15%, about 16%, about 17%, about 18%, about 19%,about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% byweight. In one embodiment, the sustained release delivery systemincludes the cross-linking agent in an amount of about 18% by weight. Inone embodiment, the sustained release delivery system includes thecross-linking agent in an amount of about 12% by weight. In oneembodiment, the sustained release delivery system includes thecross-linking agent in an amount of about 30% by weight. In oneembodiment, the sustained release delivery system includes thecross-linking agent in an amount of about 42% by weight.

Exemplary cross-linking agents include homopolysaccharides. Exemplaryhomopolysaccharides include without limitation galactomannan gums, suchas guar gum, hydroxypropyl guar gum, and locust bean gum. In someembodiments, the cross-linking agent is a locust bean gum or a guar gum.In other embodiments, the cross-linking agent is an alginic acidderivative or hydrocolloid.

In some embodiments, when the sustained release delivery system includesat least one hydrophilic compound and at least one cross-linking agent,the weight ratio of hydrophilic compound to cross-linking agent is fromabout 1:9 to about 9:1, about 1:8 to about 8:1, about 1:7 to about 7:1,about 1:6 to about 6:1, about 1:5 to about 5:1, about 1:4 to about 4:1,about 1:3 to about 3:1, or about 1:2 to about 2:1. In some embodiments,the weight ratio of hydrophilic compound to cross-linking agent is about1:5, about 1:4.5, about 1:4, about 1:3.5, about 1:3, about 1:2.5, about1:2, about 1:1.5, and about 1:1.

When the sustained release delivery system includes at least onehydrophilic compound and at least one cross-linking agent, the weightratio of the nalbuphine or pharmaceutically acceptable salt or esterthereof to the sum of the at least one hydrophilic compound and the atleast one cross-linking agent is from about 10:1 to about 1:10, fromabout 9:1 to about 1:9, from about 8:1 to about 1:8, from about 7:1 toabout 1:7, from about 6:1 to about 1:6, from about 5:1 to about 1:5,from about 4:1 to about 1:4, from about 3:1 to about 1:3, or from about2:1 to about 1:2. In some embodiments, the weight ratio of thenalbuphine or pharmaceutically acceptable salt or ester thereof to thesum of the at least one hydrophilic compound and the at least onecross-linking agent is from about 4:1 to about 1:1, from about 4:1 toabout 1:1.5, from about 3:1 to about 1:1, or from about 2:1 to about1:1. In one embodiment, the ratio of the nalbuphine or pharmaceuticallyacceptable salt or ester thereof to the sum of the at least onehydrophilic compound and the at least one cross-linking agent is about5:1, about 4:1 (i.e., 1:0.25), about 3.5:1, about 3:1, about 2.5:1,about 2:1 (i.e., 1:0.5), about 1.9:1, about 1.8:1, about 1.7:1, about1.6:1, about 1.5:1, about 1.4:1, about 1.3:1, about 1.2:1, about 1.1:1,about 1:1, about 1:1.5, about 1:2, about 1:3, about 1:4, and about 1:5.

The sustained release delivery system further includes one or morepharmaceutical diluents known in the art. Exemplary pharmaceuticaldiluents include without limitation monosaccharides, disaccharides,polyhydric alcohols and mixtures thereof. In some embodiments,pharmaceutical diluents include, for example, starch, mannitol, lactose,dextrose, sucrose, microcrystalline cellulose, sorbitol, xylitol,fructose, and mixtures thereof. In some embodiments, the pharmaceuticaldiluent is water-soluble. Nonlimiting examples of water-solublepharmaceutical diluents include lactose, dextrose, sucrose, or mixturesthereof. The weight ratio of pharmaceutical diluent to hydrophiliccompound is generally from about 1:9 to about 9:1, from about 1:8 toabout 8:1, from about 1:7 to about 7:1, from about 1:6 to about 6:1,from about 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3to about 3:1, or from about 1:2 to about 2:1. In some embodiments, theweight ratio of pharmaceutical diluent to hydrophilic compound isgenerally from about 9:1 to about 1:1.5. In some embodiments, the weightratio of pharmaceutical diluent to hydrophilic compound is about 9:1,about 8.75:1, about 8.5:1, about 8.25:1, about 8:1, about 7.5:1, about7:1, about 6.5:1, about 6:1, about 5.5:1, about 5:1, about 4.5:1, about4:1, about 3.5:1, about 3:1, about 2.5:1, about 2:1, about 1.5:1, orabout 1:1.

The sustained release delivery system generally includes one or morepharmaceutical diluents in an amount of about 20% to about 80%, about30% to about 70%, about 40% to about 70%, or about 40% to about 60%. Inone embodiment, the sustained release delivery system includes one ormore pharmaceutical diluents in an amount of about 20% to about 70% byweight. In one embodiment, the sustained release delivery systemincludes one or more pharmaceutical diluents in an amount of about 50%to about 85% by weight. In some embodiments, the sustained releasedelivery system includes one or more pharmaceutical diluents in anamount of about 55%, about 60%, about 65%, about 70%, about 80%, orabout 85% by weight. In one embodiment, the sustained release deliverysystem includes one or more pharmaceutical diluents in an amount ofabout 20% by weight. In one embodiment, the sustained release deliverysystem includes one or more pharmaceutical diluents in an amount ofabout 30% by weight. In one embodiment, the sustained release deliverysystem includes one or more pharmaceutical diluents in an amount ofabout 40% by weight. In one embodiment, the sustained release deliverysystem includes one or more pharmaceutical diluents in an amount ofabout 50% by weight. In one embodiment, the sustained release deliverysystem includes one or more pharmaceutical diluents in an amount ofabout 60% by weight. In one embodiment, the sustained release deliverysystem includes one or more pharmaceutical diluents in an amount ofabout 70% by weight.

In a further aspect, the sustained release delivery system includes oneor more cationic cross-linking compounds. In some embodiments, the oneor more cationic cross-linking compounds are used instead of thecross-linking agent. In some embodiments, the one or more cationiccross-linking compounds are used in addition to the cross-linking agent.In one embodiment, the one or more cationic cross-linking compounds areused in an amount sufficient to cross-link the hydrophilic compound toform a gel matrix in the presence of liquids. In some embodiments, theone or more cationic cross-linking compounds are present in thesustained release delivery system in an amount of about 0.5% to about30%, about 0.5% to about 25%, about 0.5% to about 20%, about 0.5% toabout 15%, about 0.5% to about 10%, or about 0.5% to about 5% by weight.In some embodiments, the one or more cationic cross-linking compoundsare present in the sustained release delivery system in an amount ofabout 5% to about 20%, about 5% to about 15%, about 6% to about 14%,about 7% to about 13%, about 8% to about 12%, or about 9% to about 11%by weight. In some embodiments, the one or more cationic cross-linkingcompounds are present in the sustained release delivery system in anamount of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%,about 11%, about 12%, about 13%, about 14%, or about 15% by weight. Inone embodiment, the cationic cross-linking compound is present in thesustained release delivery system in an amount of about 10% by weight.

Exemplary cationic cross-linking compounds include without limitationmonovalent metal cations, multivalent metal cations, and inorganicsalts, including alkali metal and/or alkaline earth metal sulfates,chlorides, borates, bromides, citrates, acetates, lactates, and mixturesthereof. For example, the cationic cross-linking compound includewithout limitation one or more of calcium sulfate, sodium chloride,potassium sulfate, sodium carbonate, lithium chloride, tripotassiumphosphate, sodium borate, potassium bromide, potassium fluoride, sodiumbicarbonate, calcium chloride, magnesium chloride, sodium citrate,sodium acetate, calcium lactate, magnesium sulfate, sodium fluoride, ormixtures thereof.

When the sustained release delivery system includes at least onehydrophilic compound and at least one cationic cross-linking compound,the weight ratio of hydrophilic compound to cationic cross-linkingcompound ranges from about 1:9 to about 9:1, from about 1:8 to about8:1, from about 1:7 to about 7:1, from about 1:6 to about 6:1, fromabout 1:5 to about 5:1, from about 1:4 to about 4:1, from about 1:3 toabout 3:1, or from about 1:2 to about 2:1. In one embodiment, the weightratio of hydrophilic compound to cationic cross-linking compound rangesfrom about 1:3 to about 3:1. In some embodiments, the weight ratio ofhydrophilic compound to cationic cross-linking compound is about 3:1,about 2.75:1, about 2.5:1, about 2.25:1, about 2:1, about 1.8:1, about1.6:1, about 1.4:1, about 1.2:1, about 1:1, about 1:1.25, about 1:1.5,or about 1:2. In one embodiment, the weight ratio of hydrophiliccompound to cationic cross-linking compound is about 1:1.25. In oneembodiment, the weight ratio of hydrophilic compound to cationiccross-linking compound is about 1.2:1. In one embodiment, the weightratio of hydrophilic compound to cationic cross-linking compound isabout 2:1. In one embodiment, the weight ratio of hydrophilic compoundto cationic cross-linking compound is about 2.8:1.

In one embodiment, the at least one hydrophilic compound is present inthe sustained release delivery system in an amount of about 5% to about80% by weight; the at least one cationic cross-linking agent is presentin the sustained release delivery system in an amount of about 0.5% toabout 30% by weight; and the at least one pharmaceutical diluent ispresent in the sustained release delivery system in an amount of about20% to about 80% by weight. In another embodiment, the at least onehydrophilic compound is present in the sustained release delivery systemin an amount of about 8% to about 30% by weight; the at least onecationic cross-linking agent is present in the sustained releasedelivery system in an amount of about 10% by weight; and the at leastone pharmaceutical diluent is present in the sustained release deliverysystem in an amount of about 20% to about 70% by weight. In anotherembodiment, the at least one hydrophilic compound is present in thesustained release delivery system in an amount of about 5% to about 30%by weight; the at least one cationic cross-linking agent is present inthe sustained release delivery system in an amount of about 5% to about20% by weight; and the at least one pharmaceutical diluent is present inthe sustained release delivery system in an amount of about 20% to about85% by weight. In another embodiment, the at least one hydrophiliccompound is present in the sustained release delivery system in anamount of about 10% to about 20% by weight; the at least one cationiccross-linking agent is present in the sustained release delivery systemin an amount of about 5% to about 15% by weight; and the at least onepharmaceutical diluent is present in the sustained release deliverysystem in an amount of about 50% to about 85% by weight.

In some embodiments, the at least one hydrophilic compound is present inthe sustained release delivery system in an amount of about 8%, about9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%,about 16%, about 17%, about 18%, about 19%, about 20%, about 22%, about24%, about 26%, about 28%, or about 30% by weight; the at least onecationic cross-linking agent is present in the sustained releasedelivery system in an amount of about 5%, about 6%, about 7%, about 8%,about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about15%, about 16%, about 17%, about 18%, about 19%, or about 20%, byweight; and the at least one pharmaceutical diluent is present in thesustained release delivery system in an amount of about 40%, about 45%,about 50%, about 55%, about 60%, about 65%, about 70%, about 80%, orabout 85% by weight. In one embodiment, the at least one hydrophiliccompound is present in the sustained release delivery system in anamount of about 10%, about 11%, about 12%, about 13%, about 14%, about15%, about 16%, about 17%, about 18%, about 19%, or about 20% by weight;the at least one cationic cross-linking agent is present in thesustained release delivery system in an amount of about 5%, about 6%,about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about13%, about 14%, about 15%, by weight; and the at least onepharmaceutical diluent is present in the sustained release deliverysystem in an amount of about 55%, about 60%, about 65%, about 70%, about80%, or about 85% by weight. In one embodiment, the at least onehydrophilic compound is present in the sustained release delivery systemin an amount of about 8%, about 12%, or about 20% by weight; the atleast one cationic cross-linking agent is present in the sustainedrelease delivery system in an amount of about 10%, about 12%, or about14% by weight; and the at least one pharmaceutical diluent is present inthe sustained release delivery system in an amount of about 40%, about60%, or about 70% by weight.

In one embodiment, the sustained release delivery system includes about0.5% to about 80% locust bean gum, about 5% to about 80% xanthan gum,about 20% to about 80% mannitol and about 0.5% to 80% calcium sulfatedihydrate. In one embodiment, the sustained release delivery systemincludes about 12% to about 47% locust bean gum, about 8% to about 31%xanthan gum, about 20% to about 78% mannitol and about 0.5% to 25%calcium sulfate dihydrate. In one embodiment, the sustained releasedelivery system includes about 15% to about 25% locust bean gum, about10% to about 20% xanthan gum, about 50% to about 85% mannitol and about5% to 15% calcium sulfate dihydrate. In one embodiment, the sustainedrelease delivery system includes about 18% locust bean gum, about 12%xanthan gum, about 60% mannitol and about 10% calcium sulfate dihydrate.In one embodiment, the sustained release delivery system includes about12% locust bean gum, about 8% xanthan gum, about 70% mannitol and about10% calcium sulfate dihydrate. In one embodiment, the sustained releasedelivery system includes about 20% locust bean gum, about 30% xanthangum, about 40% mannitol and about 10% calcium sulfate dihydrate. In oneembodiment, the sustained release delivery system includes about 30%locust bean gum, about 20% xanthan gum, about 40% mannitol and about 10%calcium sulfate dihydrate. In one embodiment, the sustained releasedelivery system includes about 42% locust bean gum, about 28% xanthangum, about 20% mannitol and about 10% calcium sulfate dihydrate.

Two properties of the components of this sustained release system (e.g.,the at least one hydrophilic compound and the at least one cross-linkingagent; or the at least one hydrophilic compound and at least onecationic cross-linking compound) are that it forms a gel matrix uponexposure to liquids are fast hydration of the compounds/agents and theability to form a gel matrix having a high gel strength. These twoproperties, which are needed to achieve a slow release gel matrix, aremaximized by the particular combination of compounds (e.g., the at leastone hydrophilic compound and the at least one cross-linking agent; orthe at least one hydrophilic compound and the at least one cationiccross-linking compound). For example, hydrophilic compounds (e.g.,xanthan gum) have excellent water-wicking properties that provide fasthydration. The combination of hydrophilic compounds with materials thatare capable of cross-linking the rigid helical ordered structure of thehydrophilic compound (e.g., cross-linking agents and/or cationiccross-linking compounds) thereby acts synergistically to provide ahigher than expected viscosity (i.e., high gel strength) of the gelmatrix.

In some embodiments, the sustained release compositions are furtheradmixed with one or more wetting agents (e.g., polyethoxylated castoroil, polyethoxylated hydrogenated castor oil, polyethoxylated fatty acidfrom castor oil, polyethoxylated fatty acid from hydrogenated castoroil) one or more lubricants (e.g., magnesium stearate, sodium stearylfumarate, and the like), one or more buffering agents, one or morecolorants, and/or other conventional ingredients.

In some embodiments compositions employed in the present methods cancontain additional pharmaceutical excipients. For example, in certainembodiments, fumaric acid can be added to the formulations describedherein.

In other embodiments, a non-functional coating, e.g., Opadry®, can beadded to the compositions described herein.

In some embodiments, the compositions described herein further include asecond hydrophilic compound. In some embodiments, the second hydrophiliccompound is a cellulose ether. In some embodiments, the secondhydrophilic compound is a hydroxyalkyl cellulose or a carboxyalkylcellulose. In some embodiments, the second hydrophilic compound is ahydroxyethyl cellulose, a hydroxypropyl cellulose, ahydroxypropylmethyl-cellulose, a carboxy methylcellulose, or a mixturethereof. In some embodiments, the second hydrophilic is an ethylcellulose or wax (e.g., including without limitation cetyl alcohol,stearyl alcohol, white wax, or carnauba wax). The second hydrophiliccompound is present in the formulation in an amount ranging from about5% to about 45%, about 5% to about 25%, about 10% to about 20%, or 12%to about 18% by weight. In some embodiments, the second hydrophiliccompound is present in the formulation in an amount of about 5%, about6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%,about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about30%, about 35%, about 40%, or about 45%.

In some embodiments, the weight ratio of the second hydrophilic compoundto the nalbuphine or pharmaceutically acceptable salt or ester rangesfrom about 5:1 to about 1:5, about 4:1 to about 1:4, about 3:1 to about1:3, about 2:1 to about 1:2, about 1:1 to about 1:3, or about 1:1 toabout 1:2. In some embodiments, the weight ratio of the secondhydrophilic compound to the nalbuphine or pharmaceutically acceptablesalt or ester is about 5:1, about 4:1, about 3:1, about 2:1, about 1:1,about 1:2, about 1:3, about 1:4, or about 1:5.

In some embodiments, the weight ratio of the second hydrophilic compoundto the sustained release delivery system ranges from about 10:1 to about1:10, about 8:1 to about 1:8, about 6:1 to about 1:6, about 4:1 to about1:4, about 2:1 to about 1:3, about 1:1 to about 1:10, about 1:1 to about1:6, or about 1:2 to about 1:6. In some embodiments, the weight ratio ofthe second hydrophilic compound to the sustained release delivery systemis about 10:1, about 8:1, about 6:1, about 4:1, about 2:1, about 1:1,about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:4, about 1:5,about 1:6, about 1:7, about 1:8, about 1:9 or about 1:10.

In some embodiments, the oral sustained release solid dosageformulations including from about 1 mg to 200 mg nalbuphinehydrochloride and about 10 mg to about 420 mg of a sustained releasedelivery system. In these embodiments, the sustained release deliverysystem includes about 12% to about 42% locust bean gum; about 8.0% toabout 28% xanthan gum; about 20% to about 70% mannitol; and about 5% toabout 20% calcium sulfate dihydrate. In some embodiments, the presentmethods can employ oral sustained release solid dosage formulationsincluding from about 5 mg to about 80 mg nalbuphine hydrochloride andabout 80 mg to about 360 mg of a sustained release delivery system. Insome embodiments, the present methods can employ oral sustained releasesolid dosage formulations including from about 50 mg to about 150 mgnalbuphine hydrochloride and about 100 mg to about 300 mg of a sustainedrelease delivery system.

In some embodiments, the present methods employ oral sustained releasesolid dosage formulations including about 15 mg nalbuphinehydrochloride, and from about 25 mg to about 225 mg, for example about195 mg, of a sustained release delivery system. In these embodiments,the sustained release delivery system includes about 14% locust beangum; about 9% xanthan gum; about 47% mannitol; and about 8% calciumsulfate dihydrate.

In some embodiments, the present methods employ oral sustained releasesolid dosage formulations including about 30 mg nalbuphinehydrochloride, and from about 25 mg to about 225 mg, for example about180 mg, of a sustained release delivery system. In these embodiments,the sustained release delivery system includes about 18% locust beangum; about 12% xanthan gum; about 60% mannitol; and about 10% calciumsulfate dihydrate.

In some embodiments, the present methods employ oral sustained releasesolid dosage formulations including about 60 mg nalbuphinehydrochloride, and from about 25 mg to about 225 mg, for example about120 mg, of a sustained release delivery system. In these embodiments,the sustained release delivery system includes about 10% locust beangum; about 12% xanthan gum; about 60% mannitol; and about 10% calciumsulfate dihydrate. In some embodiments, the present methods employ oralsustained release solid dosage formulations including from about 5 mg toabout 80 mg nalbuphine hydrochloride and about 80 mg to about 360 mg ofa sustained release delivery system.

In some embodiments, the present methods employ oral sustained releasesolid dosage formulations including about 120 mg nalbuphinehydrochloride, and from about 25 mg to about 250 mg, for example about240 mg, of a sustained release delivery system. In these embodiments,the sustained release delivery system includes about 18% locust beangum; about 12% xanthan gum; about 60% mannitol; and about 10% calciumsulfate dihydrate.

In some embodiments, the present methods employ oral sustained releasesolid dosage formulations including about 30 mg nalbuphinehydrochloride, and from about 25 mg to about 350 mg, for example about270 mg or about 360 mg, of a sustained release delivery system. In theseembodiments, the sustained release delivery system includes about 18%locust bean gum; about 12% xanthan gum; about 60% mannitol; and about10% calcium sulfate dihydrate.

In some embodiments, the present methods employ oral sustained releasesolid dosage formulations including about 45 to about 60 mg nalbuphinehydrochloride and from about 100 mg to about 200 mg of a sustainedrelease delivery system. In these embodiments, the sustained releasedelivery system includes about 15% to about 25% locust bean gum; about10% to about 20% xanthan gum; about 50% to about 85% mannitol; and about5% to about 15% calcium sulfate dihydrate.

In some embodiments, the present methods employ oral sustained releasesolid dosage formulations including about 30 mg nalbuphinehydrochloride, about 32.4 mg locust bean gum; about 21.6 mg xanthan gum;about 108 mg mannitol; about 18 mg calcium sulfate dihydrate, about 35mg hydroxypropylcellulose, and about 1.9 mg magnesium stearate.

In some embodiments, the present methods employ oral sustained releasesolid dosage formulations including about 60 mg nalbuphinehydrochloride, about 21.6 mg locust bean gum; about 14.4 mg xanthan gum;about 72 mg mannitol; about 12 mg calcium sulfate dihydrate, about 30 mghydroxypropylcellulose, and about 1.6 mg magnesium stearate.

In some embodiments, the present methods employ oral sustained releasesolid dosage formulations including about 120 mg nalbuphinehydrochloride, about 43.2 mg locust bean gum; about 28.8 mg xanthan gum;about 144 mg mannitol; about 24 mg calcium sulfate dihydrate, about 60mg hydroxypropylcellulose, and about 3.2 mg magnesium stearate.

In some embodiments, the present methods employ oral sustained releasesolid dosage formulations including about 180 mg nalbuphinehydrochloride, about 64.8 mg locust bean gum; about 43.2 mg xanthan gum;about 216 mg mannitol; about 36 mg calcium sulfate dihydrate, about 90mg hydroxypropylcellulose, about 5 mg magnesium stearate, and about 25mg fumaric acid.

In some embodiments, the present methods employ oral sustained releasesolid dosage formulations including about 180 mg nalbuphinehydrochloride, about 48.6 mg locust bean gum; about 32.4 mg xanthan gum;about 162 mg mannitol; about 27 mg calcium sulfate dihydrate, about 60mg hydroxypropylcellulose, about 4 mg magnesium stearate, and about 25mg fumaric acid.

In some embodiments, the present methods employ oral sustained releasesolid dosage formulations including about 30 mg nalbuphinehydrochloride, about 32.4 mg locust bean gum; about 21.6 mg xanthan gum;about 108 mg mannitol; about 18 mg calcium sulfate dihydrate, about 35mg hydroxypropylcellulose, about 1.9 mg magnesium stearate, and about7.4 mg Opadry II White.

The sustained release formulations of nalbuphine are orallyadministrable solid dosage formulations. Nonlimiting examples of oralsolid dosage formulations include tablets, capsules including aplurality of granules, sublingual tablets, powders, granules, syrups,and buccal dosage forms or devices (e.g., buccal patches, tablets,etc.). In some embodiments, tablets have an enteric coating or ahydrophilic coating.

The sustained release delivery system is prepared by dry granulation orwet granulation, before the nalbuphine or pharmaceutically acceptablesalt or ester thereof is added, although the components can be heldtogether by an agglomeration technique to produce an acceptable product.In the wet granulation technique, the components (e.g., hydrophiliccompounds, cross-linking agents, pharmaceutical diluents, cationiccross-linking compounds, hydrophobic polymers, etc.) are mixed togetherand then moistened with one or more liquids (e.g., water, propyleneglycol, glycerol, alcohol) to produce a moistened mass that issubsequently dried. The dried mass is then milled with conventionalequipment into granules of the sustained release delivery system.Thereafter, the sustained release delivery system is mixed in thedesired amounts with the nalbuphine or the pharmaceutically acceptablesalt or ester thereof and, optionally, one or more wetting agents, oneor more lubricants, one or more buffering agents, one or more coloringagents, one or more second hydrophilic compounds, or other conventionalingredients, to produce a granulated composition. The sustained releasedelivery system and the nalbuphine can be blended with, for example, ahigh shear mixer. The nalbuphine is preferably finely and homogeneouslydispersed in the sustained release delivery system. The granulatedcomposition, in an amount sufficient to make a uniform batch of tablets,is subjected to tableting in a conventional production scale tabletingmachine at typical compression pressures, i.e., about 2,000-16,000 psi.In some embodiments, the mixture should not be compressed to a pointwhere there is subsequent difficulty with hydration upon exposure toliquids.

In some embodiments, the nalbuphine formulation is prepared by drygranulation or wet granulation. The components of the sustained releasedelivery system are added, along with the nalbuphine or apharmaceutically acceptable salt or ester thereof. Alternatively, all ofthe components can be held together by an agglomeration technique toproduce an acceptable product. In the wet granulation technique,nalbuphine or pharmaceutically salt or ester thereof and the components(e.g., hydrophilic compounds, cross-linking agents, pharmaceuticaldiluents, cationic cross-linking compounds, hydrophobic polymers, etc.)are mixed together and then moistened with one or more liquids (e.g.,water, propylene glycol, glycerol, alcohol) to produce a moistened massthat is subsequently dried. The dried mass is then milled withconventional equipment into granules. Optionally, one or more wettingagents, one or more lubricants, one or more buffering agents, one ormore coloring agents, one or more second hydrophilic compounds, or otherconventional ingredients, are also added to the granulation. Thegranulated composition, in an amount sufficient to make a uniform batchof tablets, is subjected to tableting in a conventional production scaletableting machine at typical compression pressures, i.e., about2,000-16,000 psi. In some embodiments, the mixture should not becompressed to a point where there is subsequent difficulty withhydration upon exposure to liquids.

The average particle size of the granulated composition is from about 50μm to about 400 gm by weight. In some embodiments, the average particlesize by weight is from about 185 μm to about 265 μm. The average densityof the granulated composition is from about 0.3 g/mL to about 0.8 g/mL.In some embodiments, the average density is from about 0.5 g/mL to about0.7 g/mL. The tablets formed from the granulations are generally fromabout 4 Kp to about 22 Kp hardness. The average flow of the granulationsis from about 25 to about 40 g/sec.

In some embodiments, the present methods can employ a multilayer soliddosage form, in which the layers are formulated to release thenalbuphine hydrochloride at different rates. For example, in oneembodiment, the second layer is an extended release layer that includesnalbuphine or a pharmaceutically acceptable salt or ester thereof and asustained release delivery system designed to release the nalbuphine orthe pharmaceutically acceptable salt or ester thereof at a controlledrate so that therapeutically beneficial blood levels are maintained overan extended period of time (e.g., from about 8 to about 12 hours). Thefirst layer is an immediate release layer that includes a formulation ofnalbuphine or a pharmaceutically acceptable salt or ester thereofdesigned to release the nalbuphine or the pharmaceutically acceptablesalt or ester thereof at a rate that is faster than the rate of thesecond layer to achieve a therapeutically beneficial blood level in animmediate period of time (e.g., from about 1 to about 2 hours). In someembodiments, the first layer includes a sustained release deliverysystem. In some embodiments, the first layer does not include asustained release delivery system.

In some embodiments, the weight ratio of the second layer to the firstlayer is about 10:1 to about 1:10, about 9:1 to about 1:9, about 8:1 toabout 1:8, about 7:1 to about 1:7, about 6:1 to about 1:6, about 5:1 toabout 1:5, about 4:1 to about 1:4, about 3:1 to about 1:3, about 2:1 toabout 1:2. In one embodiment, the weight ratio of the second layer tothe first layer is about 5:1 to about 1:5. In a further embodiment, theweight ratio of the second layer to the first layer is about 1:1 toabout 1:2. In some embodiments, the weight ratio of the second layer tothe first layer is about 1:1, about 1:1.2, about 1:1.4, about 1:1.6,about 1:1.8, or about 1:2. In one embodiment, the weight ratio of thesecond layer to the first layer is about 1:2. In one embodiment, theweight ratio of the second layer to the first layer is about 1:1.4. Insome embodiments, the weight ratio of the second layer to the firstlayer is about 3:1, about 2.5:1, about 2:1, about 1.5:1. In oneembodiment, the weight ratio of the second layer to the first layer isabout 2.5:1.

The sustained release delivery system of the multilayer dosage formincludes (i) at least one hydrophilic compound, at least onecross-linking agent, and at least one pharmaceutical diluent; (ii) atleast one hydrophilic compound, at least one cross-linking agent, atleast one pharmaceutical diluent, and at least one cationiccross-linking agent different from the first cross-linking agent; or(iii) at least one hydrophilic compound, at least one cationiccross-linking compound, and at least one pharmaceutical diluent. In someembodiments, when the first layer includes a sustained release deliverysystem, the sustained release delivery system of the first layerincludes the same components as the sustained release delivery system ofthe second layer (e.g., both the first and second layers are one ofembodiments (i)-(iii), listed above). In other embodiments, thesustained release delivery system of the first layer includes differentcomponents as the sustained release delivery system of the second layer(e.g., the first layer is embodiment (i), listed above, while the secondlayer is embodiment (iii), listed above). It is recognized that thesustained release delivery system of either layer can be one ofembodiments (i)-(iii) listed above. Moreover, it is recognized that insome embodiments, the first layer does not include a sustained releasedelivery system.

The sustained release delivery system is generally present in the secondlayer (e.g., extended release layer) in an amount ranging from about 10mg to about 420 mg. In some embodiments, the sustained release deliverysystem is present in the second layer in an amount ranging from about110 mg to about 200 mg. In some embodiments, the sustained releasedelivery system is present in the second layer in an amount ranging fromabout 110 mg to about 150 mg. In some embodiments, the sustained releasedelivery system is present in the second layer in an amount ranging fromabout 90 mg to about 150 mg. In some embodiments, the sustained releasedelivery system is present in the second layer in an amount of about 50mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg,about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg,about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg.In one embodiment, the sustained release delivery system is present inthe second layer in an amount of about 123 mg. In one embodiment, thesustained release delivery system is present in the second layer in anamount of about 101 mg. In one embodiment, the sustained releasedelivery system is present in the second layer in an amount of about 92mg. In another embodiment, the sustained release delivery system ispresent in the second layer in an amount of about 112.5 mg. In oneembodiment, the sustained release delivery system is present in thesecond layer in an amount of about 135 mg. In one embodiment, thesustained release delivery system is present in the second layer in anamount of about 150 mg.

Nalbuphine or a pharmaceutically acceptable salt or ester thereof isgenerally present in the second layer in an amount ranging from about 15mg to about 60 mg. In some embodiments, nalbuphine or a pharmaceuticallyacceptable salt or ester thereof is present in the second layer in anamount ranging from about 30 mg to about 60 mg. In some embodiments,nalbuphine or a pharmaceutically acceptable salt or ester thereof ispresent in the second layer in an amount ranging from about 45 mg toabout 60 mg. In one embodiment, nalbuphine or a pharmaceuticallyacceptable salt or ester thereof is present in the second layer in anamount of about 15 mg. In one embodiment, nalbuphine or apharmaceutically acceptable salt or ester thereof is present in thesecond layer in an amount of about 30 mg. In one embodiment, nalbuphineor a pharmaceutically acceptable salt or ester thereof is present in thesecond layer in an amount of about 45 mg. In one embodiment, nalbuphineor a pharmaceutically acceptable salt or ester thereof is present in thesecond layer in an amount of about 15 mg, about 30 mg, about 90 mg,about 120 mg, or about 180 mg.

In some embodiments, the weight ratio of nalbuphine or apharmaceutically acceptable salt or ester thereof to the sustainedrelease delivery system in the second layer is about 10:1 to about 1:10,about 9:1 to about 1:9, about 8:1 to about 1:8, about 7:1 to about 1:7,about 6:1 to about 1:6, about 5:1 to about 1:5, about 4:1 to about 1:4,about 3:1 to about 1:3, or about 2:1 to about 1:2. In one embodiment,the weight ratio of nalbuphine or a pharmaceutically acceptable salt orester thereof to the sustained release delivery system in the secondlayer is about 1:2 to about 1:4. In one embodiment, the weight ratio ofnalbuphine or a pharmaceutically acceptable salt or ester thereof to thesustained release delivery system in the second layer is about 1:1 toabout 1:5. In some embodiments, the weight ratio of nalbuphine or apharmaceutically acceptable salt or ester thereof to the sustainedrelease delivery system in the second layer is about 1:1, about 1:1.2,about 1:1.4, about 1:1.6, about 1:1.8, about 1:2, about 1:2.5, about1:3, or about 1:3.5. In one embodiment, the weight ratio of nalbuphineor a pharmaceutically acceptable salt or ester thereof to the sustainedrelease delivery system in the second layer is about 1:2.5. In anotherembodiment, the weight ratio of nalbuphine or a pharmaceuticallyacceptable salt or ester thereof to the sustained release deliverysystem in the second layer is about 1:3.3. In a further embodiment, theweight ratio of nalbuphine or a pharmaceutically acceptable salt orester thereof to the sustained release delivery system in the secondlayer is about 1:3. In yet another embodiment, the ratio of nalbuphineor a pharmaceutically acceptable salt or ester thereof to the sustainedrelease delivery system in the second layer is about 1:2.

When the sustained release delivery system is present in the first layer(e.g., immediate release layer), it is generally present in an amountranging from about 0 mg to about 50 mg. In some embodiments, thesustained release delivery system is present in the first layer in anamount ranging from about 5 mg to about 25 mg or from about 5 mg toabout 15 mg. In one embodiment, the sustained release delivery system ispresent in the first layer in an amount of about 3 mg to about 9 mg. Inone embodiment, the sustained release delivery system is present in thefirst layer in an amount of about 4 mg to about 6 mg. In someembodiments, the sustained release delivery system is present in thefirst layer in an amount of about 2 mg, about 4 mg, about 6 mg, about 8mg, about 10 mg, about 12 mg, about 14 mg, about 15 mg, about 16 mg,about 18 mg, about 20 mg about 25 mg, about 30 mg, about 35 mg, about 40mg, about 45 mg or about 50 mg. In one embodiment, the sustained releasedelivery system is present in the first layer in an amount of about 6mg.

In some embodiments, nalbuphine or a pharmaceutically acceptable salt orester thereof is generally present in the first layer (e.g., immediaterelease layer) in an amount ranging from about 5 mg to about 180 mg. Insome embodiments, nalbuphine or a pharmaceutically acceptable salt orester thereof is present in the first layer in an amount ranging fromabout 5 mg to about 25 mg or from about 10 mg to about 20 mg. In someembodiments, the nalbuphine or a pharmaceutically acceptable salt orester thereof is present in the first layer in an amount of about 5 mg,about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg,about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg or about50 mg. In one embodiment, nalbuphine or a pharmaceutically acceptablesalt or ester thereof is present in the first layer in an amount ofabout 15 mg, about 30 mg, about 90 mg, about 120 mg, or about 180 mg.

In some embodiments, when the first layer includes a sustained releasedelivery system, the ratio of nalbuphine or pharmaceutically acceptablesalt or ester thereof to the sustained release delivery system in thefirst layer is about 10:1 to about 1:10, about 9:1 to about 1:9, about8:1 to about 1:8, about 7:1 to about 1:7, about 6:1 to about 1:6, about5:1 to about 1:5, about 4:1 to about 1:4, about 3:1 to about 1:3, about2:1 to about 1:2. In one embodiment, the ratio of nalbuphine orpharmaceutically acceptable salt or ester thereof to the sustainedrelease delivery system in the first layer is about 2:1 to about 4:1. Insome embodiments, the ratio of nalbuphine or pharmaceutically acceptablesalt or ester thereof to the sustained release delivery system in thefirst layer is about 5:1, about 4.5:1, about 4:1, about 3.5:1, about3:1, about 2.5:1, about 2:1, about 1.5:1, or about 1:1. In oneembodiment, the ratio of nalbuphine or pharmaceutically acceptable saltor ester thereof to the sustained release delivery system in the firstlayer is about 2.5:1. In another embodiment, the ratio of nalbuphine orpharmaceutically acceptable salt or ester thereof to the sustainedrelease delivery system in the first layer is about 3:1.

In some embodiments, the multilayer dosage form further includes apharmaceutical disintegrant. The disintegrant promotes the dissolutionand absorption of nalbuphine or pharmaceutically acceptable salt orester thereof from the immediate release layer. Nonlimiting examples ofpharmaceutical disintegrants include croscarmellose sodium, starchglycolate, crospovidone, and unmodified starch. In one embodiment, thedisintegrant is in the first layer (i.e., the immediate release layer),of the dosage form. The disintegrant is generally present in the layerin an amount of about 1.5 mg to about 4.5 mg. In one embodiment, thedisintegrant is present in an amount of about 3 mg. In one embodiment,the disintegrant is present in the layer in an amount of about 2-10% byweight. In one embodiment, the disintegrant is present in the layer inan amount of about 5% by weight. When the layer contains a sustainedrelease delivery system, the weight ratio of the sustained releasedelivery system to the disintegrant is in a range of about 5:1 to about1:5. In some embodiments, the ratio of the sustained release deliverysystem to the disintegrant is in a range of about 1:1 to about 3:1. Inother embodiments, the ratio of the sustained release delivery system tothe disintegrant is in a range of about 2:1.

In some embodiments, the multilayer tablets are prepared by firstpreparing the immediate release layer and extended release layer blendsseparately. The extended release layer is prepared as described above.The wet granulation of the extended release layer is then dried andmilled to an appropriate size. Magnesium stearate is added and mixedwith the milled granulation. The immediate release layer is prepared byfirst mixing the nalbuphine or the pharmaceutically acceptable salt orester thereof with one or more diluents (e.g., microcrystallinecellulose). This mix is then optionally mixed with one or moredisintegrants. The blend is mixed with magnesium stearate. Finally, theimmediate release layer blend and the extended release layer blend arecompressed into multi-layer (e.g., bi-layer) tablets.

The invention provides methods for treating pruritus by administering aneffective amount, e.g., an effective amount of a sustained releaseformulation of nalbuphine or a pharmaceutically acceptable salt or esterthereof to a subject, e.g., human or animal patient in need thereof. Aneffective amount is an amount sufficient to eliminate or significantlyreduce pruritus symptoms or to alleviate those symptoms (e.g., reducethe symptoms, such as itching, compared to the symptoms present prior toadministration of the nalbuphine sustained release formulation).“Sustained release” or “extended release” means that the nalbuphine orpharmaceutically acceptable salt or ester thereof is released from theformulation at a controlled rate so that therapeutically beneficialblood levels (but below toxic levels) of the nalbuphine orpharmaceutically acceptable salt or ester thereof are maintained over anextended period of time. Alternatively, “sustained release” or “extendedrelease” means that the desired pharmacologic effect is maintained overan extended period of time. Clinical trials of the formulationsdescribed herein find that the duration of relief of pruritus symptomsis longer than expected. The half-life of experimental orallyadministered nalbuphine formulations (i.e., immediate releaseformulations) has been reported to be relatively short, only about 5-7hours. Moreover, the published literature suggests that the duration ofeffect for experimental formulations of immediate release nalbuphine wasonly about 4 hours. Based on these data, it was expected that asustained release formulation would provide a duration of anti-pruriticeffect for approximately 6-8 hours, i.e., allowing for 2-3 times dailydosing. In the clinical trials described herein, however, nalbuphinesustained release formulations have an anti-pruritic effect of longerthan 8 hours. In some cases, the duration of anti-pruritic effect is atleast about 12 hours, thus providing the possibility of fewer dosingadministrations.

Without wishing to be bound by a particular theory, the longer thanexpected duration of anti-pruritic effect is attributed to theenterohepatic recirculation of nalbuphine. Nalbuphine forms a glucuronicacid or other type of conjugated metabolite in vivo through enzymaticreaction with an enzyme system such as UDP-glucuronyl transferase. It isalso possible that enterohepatic recirculation also occurs when parentdrug in the bile is released from the gallbladder into the intestine andreabsorbed. Once formed, the conjugated nalbuphine product is thought tobe transported into the gastrointestinal tract via biliary secretionwhereby the drug conjugate is cleaved liberating nalbuphine which can bereabsorbed from the intestine. The sustained release formulation canimprove the duration of anti-pruritic effect, by more slowly releasingnalbuphine into the in vivo system and allowing more drug to beconjugated and therefore available for recirculation and laterreabsorption from the intestine.

In certain embodiments, the chemistry of certain of the components ofthe formulation, such as the hydrophilic compound (e.g., xanthan gum),is such that the components are considered to be self-buffering agentswhich are substantially insensitive to the solubility of the nalbuphineand the pH changes along the length of the gastrointestinal tract.Moreover, the chemistry of the components is believed to be similar tocertain known muco-adhesive substances, such as polycarbophil.Muco-adhesive properties are desirable for buccal delivery systems.Thus, the sustained release formulation can loosely interact with themucin in the gastrointestinal tract and thereby provide another mode bywhich a constant rate of delivery of the nalbuphine is achieved.

The two phenomenon discussed above (buoyancy and muco-adhesiveproperties) are mechanisms by which the sustained release formulationscan interact with the mucin and fluids of the gastrointestinal tract andprovide a constant rate of delivery of the nalbuphine.

When measured by USP Procedure Drug Release General Chapter <711>Dissolution, (incorporated by reference herein in its entirety), thesustained release formulations employed in the present methods generallyexhibit an in vitro dissolution of about 15% to about 50% by weightnalbuphine after 1 hour, about 45% to about 80% by weight nalbuphineafter 4 hours, or at least about 80% by weight nalbuphine after 10hours. In some embodiments, the in vitro and in vivo releasecharacteristics of the sustained release formulations are modified usingmixtures of one or more different water insoluble and/or water solublecompounds, using different plasticizers, varying the thickness of thesustained release film, including providing release-modifying compoundsin the coating, and/or by providing passageways through the coating. Insome embodiments, the dissolution rate is determined using apparatus USPType III/250 mL at pH 6.8, 37° C. and 15 dpm. In some embodiments, thedissolution rate is determined using apparatus USP Type III/250 mLperformed in pH change (0-1 hours pH 1.2, after hour 1 pH 4.5, afterhour 2 pH 6.8) at 37° C. and 15 dpm.

In some embodiments, the sustained release formulation has an in vitrodissolution of about 50% to about 100% by weight nalbuphine after about6 hours. In some embodiments, the sustained release formulation has anin vitro dissolution of about 75% to about 100% by weight nalbuphineafter about 6 hours. In other embodiments, the sustained releaseformulation has an in vitro dissolution of about 75% to about 100% byweight nalbuphine from about 6 hours to about 8 hours. In furtherembodiments, the sustained release formulation has an in vitrodissolution of about 80% to about 100% by weight nalbuphine after about12 hours. In still other embodiments, the sustained release formulationhas an in vitro dissolution of about 80% to about 100% by weightnalbuphine from about 12 hours to about 24 hours. In some embodiments,the sustained release formulation has an in vitro dissolution of about80% to about 100% after about 8 hours to about 12 hours. In yet otherembodiments, the sustained release formulation has an in vitrodissolution of about 15% to about 75% by weight nalbuphine after about 1hour. In still further embodiments, the sustained release formulationhas an in vitro dissolution of about 50% by weight nalbuphine afterabout 1 hour. In some embodiments, the sustained release formulation hasan in vitro dissolution of about 50% by weight nalbuphine after about 1hour and about 75% to about 100% by weight nalbuphine from about 6 hoursto about 8 hours. In some embodiments, the sustained release formulationhas an in vitro dissolution of about 50% by weight nalbuphine afterabout 1 hour and about 75% to about 100% by weight nalbuphine from about8 hours to about 12 hours. In some embodiments, the sustained releaseformulation has an in vitro dissolution of about 50% by weightnalbuphine after about 1 hour and about 75% to about 100% by weightnalbuphine from about 12 hours to about 24 hours. In some embodiments,the sustained release formulation has an in vitro dissolution of about50% by weight nalbuphine after about 1 hour and about 80% to about 100%by weight nalbuphine after about 12 hours.

Where the tablet is a multilayer dosage form having a first extendedrelease layer and a second, immediate release, layer, the sustainedrelease formulation has an in vitro dissolution of about 25% to about75% by weight nalbuphine after about 1 hour. In some embodiments, themultilayer dosage form has an in vitro dissolution of about 25% byweight nalbuphine after about 1 hour. In some embodiments, themultilayer dosage form has an in vitro dissolution of about 50% byweight nalbuphine after about 1 hour. In some embodiments, themultilayer dosage form has an in vitro dissolution of about 75% to about100% nalbuphine after about 6-8 hours. In some embodiments, themultilayer dosage form has an in vitro dissolution of about 75% to about100% nalbuphine after about 8-12 hours. In some embodiments, themultilayer dosage form has an in vitro dissolution of about 75% to about100% nalbuphine after about 12-24 hours. In some embodiments, themultilayer dosage form has an in vitro dissolution of about 75% to about100% nalbuphine after about 12 hours.

When administered orally to patients having either normal or impaired(e.g., reduced) kidney function, the sustained release formulationsdescribed herein exhibit the following in vivo characteristics: (a) apeak plasma level of nalbuphine occurs within about 4 hours to about 6hours, e.g., for subjects with uremic pruritus or renal impairment, orabout 3 hours to about 5 hours, e.g., for subjects without renalimpairment after administration; (b) onset of nalbuphine anti-pruriticeffect from about 30 minutes of dosing to within about 6 hours ofdosing; (c) duration of the nalbuphine anti-pruritic effect is about 2to about 24 hours; and (d) the relative nalbuphine bioavailability isabout 0.5, about 1, about 1.5 or between about 0.5 to about 1.5 comparedto an orally administered aqueous solution of nalbuphine. The time ofonset for an anti-pruritic effect can depend on at least on dosing andthe severity of pruritic symptoms. In some embodiments, the duration ofthe nalbuphine anti-pruritic effect is at least about 8 hours. In someembodiments, the duration of the nalbuphine anti-pruritic effect is atleast about 9 hours. In some embodiments, the duration of the nalbuphineanti-pruritic effect is at least about 10 hours. In some embodiments,the duration of the nalbuphine anti-pruritic effect is at least about 11hours. In some embodiments, the duration of the nalbuphine anti-pruriticeffect is at least about 12 hours. In some embodiments, the duration ofnalbuphine anti-pruritic effect is about 6, hours, 8 hours, 10 hours, 12hours, 15 hours, or 18 hours. In some embodiments, the relativenalbuphine bioavailability is about 0.94 compared to an orallyadministered aqueous solution of nalbuphine. In some embodiments, therelative nalbuphine bioavailability is about 1.35 compared to an orallyadministered aqueous solution of nalbuphine.

In some embodiments, the sustained release nalbuphine formulationsprovide an oral unit dosage form including nalbuphine or apharmaceutically acceptable salt or ester thereof. The oral dosage formprovides an anti-pruritic effect over a period of at least about 6hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours,about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours,about 20 hours, about 21 hours, about 22 hours, about 23 hours or about24 hours. In some embodiments, the oral dosage form provides ananti-pruritic effect over a period of about 6-18 hours, about 8-16hours, about 8-12 hours, about 8 to about 24 hours, about 12 to about 24hours, about 18 to about 24 hours, or about 8-10 hours. The oral dosageform provides an anti-pruritic effect over a period of about 6 hours,about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours,about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20hours, about 21 hours, about 22 hours, about 23 hours or about 24 hours.

In one embodiment, the oral dosage form provides an anti-pruritic effectas well as breaking the cycle effect, e.g., the itchy sensation does notreturn after certain treatment period.

In some embodiments, the oral dosage form provides a blood plasma levelof nalbuphine characterized by one or more peaks followed by a plateauregion. The plateau region is characterized as having a relativelyconsistent blood plasma level of nalbuphine (e.g., the blood plasmalevel of nalbuphine does not consistently increase or decrease from timepoint to time point). In some embodiments, the plateau region ischaracterized as having a consistent average blood plasma level ofnalbuphine. The plateau region is contrasted with the region followingthe plateau region, in which the blood plasma level of nalbuphinegenerally decreases from one time point to the next. In someembodiments, the plateau region has a duration of at least about 1 hour,about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours,about 11 hours or about 12 hours. In some embodiments, the plateauregion has a duration from about 1 hour to about 12 hours, from about 2hours to about 10 hours, from about 2 hours to about 8 hours, from about2 hours to about 7 hours or from about 4 hours to about 10 hours, fromabout 4 hours to about 8 hours, or from about 4 hours to about 6 hours.In some embodiments, the blood plasma level of nalbuphine at each timepoint in the plateau region ranges from about 75% to about 125% of themean blood plasma level in the plateau region. In some embodiments, theblood plasma level of nalbuphine at each time point in the plateauregion ranges from about 80% to about 120% of the mean blood plasmalevel in the plateau region. In some embodiments, the blood plasma levelof nalbuphine at each time point in the plateau region ranges from about85% to about 115% of the mean blood plasma level in the plateau region.In some embodiments, the blood plasma level of nalbuphine at each timepoint in the plateau region ranges from about 90% to about 110% of themean blood plasma level in the plateau region.

In some embodiments, the minimum blood plasma level of nalbuphineobserved during the plateau region is not more than about 25% below themean blood plasma level for all time points in the plateau region. Insome embodiments, the minimum blood plasma level of nalbuphine observedduring the plateau region is not more than about 20% below the meanblood plasma level in the plateau region. In some embodiments, theminimum blood plasma level of nalbuphine observed during the plateauregion is not more than about 15% below the mean blood plasma level inthe plateau region. In some embodiments, the minimum blood plasma levelof nalbuphine observed during the plateau region ranges from about 75%to about 100% of the mean blood plasma level in the plateau region. Insome embodiments, the minimum blood plasma level of nalbuphine observedduring the plateau region ranges from about 80% to about 100% of themean blood plasma level in the plateau region. In some embodiments, theminimum blood plasma level of nalbuphine observed during the plateauregion ranges from about 85% to about 100% of the mean blood plasmalevel in the plateau region. In some embodiments, the minimum bloodplasma level of nalbuphine observed during the plateau region rangesfrom about 80% to about 95% of the mean blood plasma level in theplateau region.

Co-Therapy

While the compositions can be administered as the sole activepharmaceutical ingredient or sole active anti-pruritus ingredient in themethods described herein, in other embodiments they can also be used incombination with one or more ingredients which are known to betherapeutically effective against pruritus and/or compliment the effectof anti-pruritus ingredient.

For example, in some embodiments, the present methods can employnalbuphine or a pharmaceutically acceptable salt or ester thereof inconjunction with one or more anti-pruritic agents. In some embodiments,additional compounds combined with the anti-pruritic agent, e.g.,nalbuphine, or a pharmaceutically acceptable salt or ester thereof,include antihistamines, anti-inflammatory corticosteroids, topicalanti-infectives and antifungals, antibacterials, and antivirals,cytotoxic agents, and counter-irritants/analgesics. Other antipruriticagents include anti-depressants, vitamin D, kappa agonists, irritantssuch as coal tar derivatives and psoralens, 5-HT3 antagonists such asondansetron, H2 receptor antagonist such as cimetidine, H1 receptorantagonist such as cetirizine, immunomodulators such as tacrolimus,immunosupressants such as cyclosporine A, μ-antagonists, capsaicin,cannabinoids, latex extracts from various Croton species found in theAmazon jungle (e.g., Zangrado®), or Nk1 antagonists, etc. In someembodiments, nalbuphine or a pharmaceutically acceptable salt or esterthereof is not administered in combination with a second anti-pruritusagent, e.g., co-formulated or administered separately.

Dosing

Formulations employed in the present methods can incorporate nalbuphinein a controlled release formulation such that the formulation providestherapeutically effective blood plasma levels of nalbuphine for thetreatment of pruritus. A dosing regimen can be selected foradministration of the formulation on a once a day basis, a twice a daybasis, thrice a day basis, or four times a day basis. The frequency ofdosing can be selected to provide a target plasma concentration ofnalbuphine to provide effective relief of the symptoms of pruritus.

In some embodiments, the total daily dose of nalbuphine, either as asingle dose or as the sum of two, three or four doses, can range fromabout 15 mg a day to about 480 mg a day (e.g., about 15 mg a day, about20 mg a day, about 25 mg a day, about 30 mg a day, about 35 mg a day,about 40 mg a day, about 45 mg a day, about 50 mg a day, about 55 mg aday, about 60 mg a day, about 65 mg a day, about 70 mg a day, about 75mg a day, about 80 mg a day, about 85 mg a day, about 90 mg a day, about95 mg a day, about 100 mg a day, about 105 mg a day, about 110 mg a day,about 115 mg a day, about 120 mg a day, about 125 mg a day, about 130 mga day, about 135 mg a day, about 140 mg a day, about 145 mg a day, about150 mg a day, about 155 mg a day, about 160 mg a day, about 165 mg aday, about 170 mg a day, about 175 mg a day, about 180 mg a day, about185 mg a day, about 190 mg a day, about 195 mg a day, about 200 mg aday, about 205 mg a day, about 210 mg a day, about 215 mg a day, about220 mg a day, about 225 mg a day, about 230 mg a day, about 235 mg aday, about 240 mg a day, about 245 mg a day, about 250 mg a day, about255 mg a day, about 260 mg a day, about 265 mg a day, about 270 mg aday, about 275 mg a day, about 280 mg a day, about 285 mg a day, about290 mg a day, about 295 mg a day, about 300 mg a day, about 305 mg aday, about 310 mg a day, about 315 mg a day, about 320 mg a day, about325 mg a day, about 330 mg a day, about 335 mg a day, about 340 mg aday, about 345 mg a day, about 350 mg a day, about 355 mg a day, about360 mg a day, about 380 mg, about 400 mg, about 420 mg, about 440 mg,about 460 mg, about 480 mg a day or any other value or range of valuestherein).

In one embodiment, the total daily dose of nalbuphine, either as asingle dose or as the sum of two, three or four doses is 15 mg, 30 mg,60 mg, 120 mg, 240 mg, 360 mg, or 480 mg. For example, the total dailydose of nalbuphine, either as a single dose or the sum of two doses is120 mg or 240 mg for the treatment of uremic pruritus. In anotherexample, the total daily dose of nalbuphine, either as a single dose orthe sum of two doses is 180 mg or 360 mg for the treatment of a subjectwho does not have any renal impairment.

In some embodiments, the maximum total daily dose of nalbuphine or apharmaceutically acceptable salt or ester thereof is about 75 mg toabout 180 mg, administered once a day, for example about 75 mg, about 80mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg,about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg,about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg,about 160 mg, about 165 mg, about 170 mg, about 175 mg, or about 180 mg,administered once a day, including all values or ranges there between.

In some embodiments, the maximum total daily dose of nalbuphine or apharmaceutically acceptable salt or ester thereof is about 90 mg toabout 360 mg, administered once a day, for example about 90 mg, about100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about250 mg, about to 60 mg, about 270 mg, about 280 mg, about 290 mg, about300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about350 mg, in about 360 mg, including all values or ranges there between.

In some other embodiments, the maximum total daily dose of nalbuphine ora pharmaceutically acceptable salt or ester thereof is about 480 mg fora subject either with renal impairment or without renal impairment.

In some embodiments, the dosing regimen is a twice-daily dose of acontrolled release formulation, and the amount of nalbuphine in thecontrolled release formulation is from about 15 mg to about 180 mg(e.g., about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg,about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg,about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg,about 170 mg, about 175 mg, about 180 mg, or any other value or range ofvalues therein). A twice-daily dosage regimen may include a total dailydosage over the two administrations of from about 15 mg a day to about360 mg a day (e.g., about 15 mg a day, about 20 mg a day, about 25 mg aday, about 30 mg a day, about 35 mg a day, about 40 mg a day, about 45mg a day, about 50 mg a day, about 55 mg a day, about 60 mg a day, about65 mg a day, about 70 mg a day, about 75 mg a day, about 80 mg a day,about 85 mg a day, about 90 mg a day, about 95 mg a day, about 100 mg aday, about 105 mg a day, about 110 mg a day, about 115 mg a day, about120 mg a day, about 125 mg a day, about 130 mg a day, about 135 mg aday, about 140 mg a day, about 145 mg a day, about 150 mg a day, about155 mg a day, about 160 mg a day, about 165 mg a day, about 170 mg aday, about 175 mg a day, about 180 mg a day, about 185 mg a day, about190 mg a day, about 195 mg a day, about 200 mg a day, about 205 mg aday, about 210 mg a day, about 215 mg a day, about 220 mg a day, about225 mg a day, about 230 mg a day, about 235 mg a day, about 240 mg aday, about 245 mg a day, about 250 mg a day, about 255 mg a day, about260 mg a day, about 265 mg a day, about 270 mg a day, about 275 mg aday, about 280 mg a day, about 285 mg a day, about 290 mg a day, about295 mg a day, about 300 mg a day, about 305 mg a day, about 310 mg aday, about 315 mg a day, about 320 mg a day, about 325 mg a day, about330 mg a day, about 335 mg a day, about 340 mg a day, about 345 mg aday, about 350 mg a day, about 355 mg a day, about 360 mg a day, or anyother value or range of values therein).

In some embodiments, a twice-daily dosage regimen may include a totaldaily dosage over the two administrations of from about 60 mg, to about120 mg, to about 240 mg, to about 360 mg or to about 480 mg.

In some embodiments, a twice-daily dosage regimen may include a totaldaily dosage over the two administrations of from about 120 mg to 240 mgfor subjects with any renal impairment or from about 180 mg to about 360mg for subject without any renal impairment.

In some embodiments, the dosing regimen is a thrice-daily dose of acontrolled release formulation, and the amount of nalbuphine in thecontrolled release formulation is from about 15 mg to about 180 mg(e.g., about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg,about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg,about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg,about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg,about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg,about 170 mg, about 175 mg, about 180 mg, or any other value or range ofvalues therein). A thrice-daily dosage regimen may include a total dailydosage over the three administrations of from about 15 mg a day to about360 mg a day (e.g., about 15 mg a day, about 20 mg a day, about 25 mg aday, about 30 mg a day, about 35 mg a day, about 40 mg a day, about 45mg a day, about 50 mg a day, about 55 mg a day, about 60 mg a day, about65 mg a day, about 70 mg a day, about 75 mg a day, about 80 mg a day,about 85 mg a day, about 90 mg a day, about 95 mg a day, about 100 mg aday, about 105 mg a day, about 110 mg a day, about 115 mg a day, about120 mg a day, about 125 mg a day, about 130 mg a day, about 135 mg aday, about 140 mg a day, about 145 mg a day, about 150 mg a day, about155 mg a day, about 160 mg a day, about 165 mg a day, about 170 mg aday, about 175 mg a day, about 180 mg a day, about 185 mg a day, about190 mg a day, about 195 mg a day, about 200 mg a day, about 205 mg aday, about 210 mg a day, about 215 mg a day, about 220 mg a day, about225 mg a day, about 230 mg a day, about 235 mg a day, about 240 mg aday, about 245 mg a day, about 250 mg a day, about 255 mg a day, about260 mg a day, about 265 mg a day, about 270 mg a day, about 275 mg aday, about 280 mg a day, about 285 mg a day, about 290 mg a day, about295 mg a day, about 300 mg a day, about 305 mg a day, about 310 mg aday, about 315 mg a day, about 320 mg a day, about 325 mg a day, about330 mg a day, about 335 mg a day, about 340 mg a day, about 345 mg aday, about 350 mg a day, about 355 mg a day, about 360 mg a day, or anyother value or range of values therein).

In some embodiments, the dosing regimen is a once-daily dose, and theamount of nalbuphine in the formulation is from about 15 mg to about 180mg (e.g., about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg,about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165mg, about 170 mg, about 175 mg, about 180 mg, or any other value orrange of values therein).

In some embodiments, irrespective of the dosing regimen, the controlledrelease formulation comprises nalbuphine or a pharmaceuticallyacceptable salt or ester thereof of about 15 mg, about 30 mg, about 60mg, about 90 mg, about 120 mg, or about 180 mg.

In some embodiments, the daily dose of nalbuphine can be selected asdescribed above, in either a once-daily dose, a twice daily dose, or athrice-daily dose, and then titrated upward until the patientexperiences satisfactory relief from the pruritic condition. Titratingthe dose can include administering a baseline daily dose, in either aonce-daily dose, a twice daily dose, or a thrice daily dose, then aftera period of observation at the baseline daily dose value to determinethe efficacy of the baseline first daily dose and/or side effectseverity, increasing the first daily dose if the subject does notexperience adequate symptom relief. The period of observation at thebaseline daily dose before increasing the daily dose can be from about 1day to about 21 days (e.g., about 1 day, about 2 days, about 3 days,about 4 days, about 5 days, about 6 days, about 7 days, about 8 days,about 9 days, about 10 days, about 11 days, about 12 days, about 13days, about 14 days, about 15 days, about 16 days, about 17 days, about18 days, about 19 days, about 20 days, about 21 days). The daily dosecan be titrated in increments ranging from about 5 mg to about 180 mg(e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg,about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg,about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, or anyother value or range of values therein). The daily dose can be titratedin one or more steps. The daily dosage can be titrated by increasing asingle daily dosage, or each dose of a twice-daily dosing regimen. Theamount a dosage is stepped, where there are multiple titration steps,can be the same, or can be different. In some embodiments, a dosage in,e.g., a twice-daily or thrice-daily dosing regimen can be titrateddownward, while the corresponding second dose (e.g., in a twice-dailyregimen) or the corresponding second and third doses (e.g., in atwice-daily regimen) can independently be held constant or increased, toreduce the total number of doses per day while retaining therapeuticefficacy.

In some embodiments, nalbuphine or a pharmaceutically acceptable salt orester is administered once a day at about 15 mg to about 30 mg, thentwice a day at about 30 mg per dose for about 2 to 3 days, and thenincreased to twice a day at about 60 mg or 120 mg per dose, e.g., forsubjects with uremic pruritus or renal impairment. In some otherembodiments, nalbuphine or a pharmaceutically acceptable salt or esteris administered once a day at about 15-30 mg, then twice a day at about30 mg per dose for about 2 to 3 days, and then increased to twice a dayat about 90 mg or 180 mg per dose, e.g., for subjects without any renalimpairment.

When nalbuphine HCl solution is administered with food, AUC isrelatively unchanged whereas Cmax values are about 1.5 fold higher inthe fed than the fasted state. Exposure (AUC) following tablets wascomparable to that from the solution with a relative bioavailability of94% under fasted state. On the other hand, with sustained releasenalbuphine formulations, Cmax was blunted (˜50%) and Tmax prolonged bothin the fed and fasted state relative to the nalbuphine HCl solution.Following oral administration of an aqueous solution, nalbuphine wasreadily absorbed with a median Tmax of 0.5-1 hr and a mean plasmahalf-life (T_(1/2)) ranging between 6.87 and 6.99 hr across studiesunder fasted conditions.

In some embodiments, the dosing frequency and dose amount peradministration are selected to provide therapeutically effective bloodplasma levels of nalbuphine for the treatment of pruritus whenadministered on a once-a-day basis. For example, in certain embodiments,the controlled release formulation, provides a mean C_(max) of fromabout 1.0 to about 120 ng/mL for example a mean C_(max) of about 1.0,about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about1.7, about 1.8, about 1.9, about 2.0, about 2.2, about 2.4, about 2.6,about 2.8, about 3.0, about 3.2, about 3.4, about 3.6, about 3.8, about4.0, about 4.2, about 4.4, about 4.6, about 4.8, about 5.0, about 5.2,about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8,about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about9.2, about 9.4, about 9.6, about 9.8, about 10, about 11, about 12,about 13, about 14, about 15, about 16, about 17, about 18, about 19,about 20, about 21, about 22, about 23, about 24, about 25, about 26,about 27, about 28, about 29, about 30, 31, about 32, about 33, about34, about 35, about 36, about 37, about 38, about 39, about 40, about41, about 42, about 43, about 44, about 45, about 46, about 47, about48, about 49, about 50, about 51, about 52, about 53, about 54, about55, about 56, about 57, about 58, about 59, about 60, about 61, about62, about 63, about 64, about 65, about 66, about 67, about 68, about69, about 70, about 71, about 72, about 73, about 74, about 75, about76, about 77, about 78, about 79, about 80, 81, about 82, about 83,about 84, about 85, about 86, about 87, about 88, about 89, about 90,about 91, about 92, about 93, about 94, about 95, about 96, about 97,about 98, about 99, about 100, about 101, about 102, about 1 to 3, about104, about 105, about 16, about 107, about 108, about 109, about 110,about 111, about 112, about 113, about 114, about 115, about 116, about117, about 118, about 119, about 120 ng/mL, or any other value or rangeof values therein.

In one embodiment, the controlled release formulation provides a meanC_(max) of from about 1.9 ng/mL to about 102 ng/mL. In anotherembodiment, the controlled release formulation provides a mean C_(max)of from about 30 ng/mL to about 60 ng/mL. In yet another embodiment, thecontrolled release formulation provides a mean C_(max) of from about 2ng/mL to about 15 ng/mL. In yet another embodiment, the controlledrelease formulation provides a mean C_(max) of from about 5 ng/mL toabout 10 ng/mL. In still other embodiments, the controlled releaseformulation provides a mean C_(max) of from about 10 ng/mL to about 20ng/mL. In still other embodiments, the controlled release formulationprovides a mean C_(max) of from about 20 ng/mL to about 30 ng/mL. Instill other embodiments, the controlled release formulation provides amean C_(max) of from about 30 ng/mL to about 50 ng/mL. In still otherembodiments, the controlled release formulation provides a mean C_(max)of from about 50 ng/mL to about 60 ng/mL.

In one embodiment, the controlled release formulation provides a meanC_(max) of from about 5 ng/mL to about 85 ng/mL, e.g., for subjects withuremic pruritus or renal impairment or from about 5 ng/mL to about 45ng/mL, e.g., for subjects without any renal impairment. For example, thecontrolled release formulation provides a mean C_(max) of from about 24ng/mL to about 71 ng/mL, e.g., for subjects with uremic pruritus orrenal impairment or from about 13 ng/mL to about 28 ng/mL, e.g., forsubjects without any renal impairment

In other embodiments, the present formulations provide a mean Cmax fromabout 0.088 (ng/mL)/mg to about 0.245 (ng/mL)/mg (e.g., about 0.08(ng/mL)/mg, about 0.09 (ng/mL)/mg, about 0.1 (ng/mL)/mg, about 0.11(ng/mL)/mg, about 0.12 (ng/mL)/mg, about 0.13 (ng/mL)/mg, about 0.14(ng/mL)/mg, about 0.15 (ng/mL)/mg, about 0.16 (ng/mL)/mg, about 0.17(ng/mL)/mg, about 0.18 (ng/mL)/mg, about 0.19 (ng/mL)/mg, about 0.20(ng/mL)/mg, about 0.21 (ng/mL)/mg, about 0.22 (ng/mL)/mg, about 0.23(ng/mL)/mg, about 0.24 (ng/mL)/mg, or any other value or range of valuestherein). In some embodiments, the present formulations provide a meanCmax from about 0.15 (ng/mL)/mg to about 0.35 (ng/mL)/mg. For example,according to the present invention the sustained release formulation canhave a mean Cmax from about 0.2 (ng/mL)/mg to about 0.3 (ng/mL)/mg.

In one embodiment, the present formulations provide a mean Cmax fromabout 0.2 (ng/mL)/mg to about 0.6 (ng/mL)/mg, e.g., for subjects withuremic pruritus or renal impairment or from about 0.15 (ng/mL)/mg toabout 0.25 (ng/mL)/mg, e.g., for subjects without any renal impairment.For example, the present formulations provide a mean Cmax from about 0.4(ng/mL)/mg to about 0.6 (ng/mL)/mg, e.g., for subjects with uremicpruritus or renal impairment or from about 0.2 (ng/mL)/mg to about 0.3(ng/mL)/mg, e.g., for subjects without any renal impairment.

In some embodiments, the dosing frequency and dose amount peradministration are selected to provide a mean C_(min) of from about 1ng/mL to about 20 ng/mL (e.g., about 1 ng/mL, about 2 ng/mL, about 3ng/mL, about 4 ng/mL, about 5 ng/mL, about 6 ng/mL, about 7 ng/mL, about8 ng/mL, about 9 ng/mL, about 10 ng/mL, about 11 ng/mL, about 12 ng/mL,about 13 ng/mL, about 14 ng/mL, about 15 ng/mL, about 16 ng/mL, about 17ng/mL, about 18 ng/mL, about 19 ng/mL, about 20 ng/mL, or any othervalue or range of values therein). In certain embodiments, the dosingfrequency and dose amount per administration are selected to provide amean C_(min) of from about 2 ng/mL to about 15 ng/mL. In otherembodiments, the dosing frequency and dose amount per administration areselected to provide a mean C_(min) of from about 5 ng/mL to about 10ng/mL, 10 ng/mL to about 20 ng/mL, 20 ng/mL to about 30 ng/mL, 30 ng/mLto about 40 ng/mL, 40 ng/mL to about 50 ng/mL or 50 ng/mL to about 60ng/mL.

In one embodiment, the dosing frequency and dose amount peradministration are selected to provide a mean C_(min) of from about 2ng/mL to about 45 ng/mL, e.g., for subjects with uremic pruritus orrenal impairment and optionally a pre AM dose or from about 0.5 ng/mL toabout 25 ng/mL for subjects without any renal impairment and optionallya pre AM dose. In another embodiment, the dosing frequency and doseamount per administration are selected to provide a mean C_(min) of fromabout 5 ng/mL to about 60 ng/mL, e.g., for subjects with uremic pruritusor renal impairment and optionally a pre PM dose or from about 2 ng/mLto about 20 ng/mL for subjects without any renal impairment andoptionally a pre PM dose.

In certain embodiments, the dosing frequency and dose amount of thecontrolled release formulation provides a nalbuphine AUC_((0-∞)) of fromabout 30 ng·hr/mL to about 950 ng·hr/mL, for example about 30, about 31,about 32, about 33, about 34, about 35, about 36, about 37, about 38,about 39, about 40, about 45, about 50, about 55, about 60, about 65,70, 75 about 80, 85, about 90, about 95, about 100, about 105, about110, about 115, about 120, about 125, about 130, about 135, about 140,about 145, about 150, about 155, about 160, 165, about 170, about 175,about 180, about 185, about 190, about 195, about 200, about 205, about210, about 215, about 220, about 225, about to 30, about 235, about 240,about 245, about 250 about 255, about 260, about 265, about 270, about275, about 280, about 285, about 290, about 295, about 300, about 305,about 310, about 315, about 320, about 325, about 330, about 335, about340, about 345, about 350, about 355, about 360, about 365, about 370,about 375, about 380, about 35, about 390, about 395, about 400, about405, about 410, about 415, about 420, about 425, about 430, about 435,about 440, about 445, about 450, about 455, about 460, about 465, about470, about 475, about 480, about 485, about 490, about 495, about 500,about 505, about 510, about 515, about 520, about 525, about 530, about535, about 540, about 545, about 550, about 555, about 560, about 565,about 570, 575, about 580, 585, about 590, about 595, about 600, about605, about 610, about 615, about 620, about 625, about 630, about 635,about 640 about 645, about 650, about 655, about 670, about 675, about680, about 685, about 690, about 695, about 700, about 705, about 710,about 715, about 720, about 725, about 730, about 735, about 740, about745, about 750, about 755, about 760, about 765, about 770, about 775,about 780, about 785, about 790, about 795, about 800, about 805, about810, about 815, about 820, about 825, about 830, about 835, about 840,about 845, about 850, about 855, about 860, but 865, about 870, about875, about 880, about 885, about 890, about 895, about 900, about 905,about 910, about 915, about 920, about 925, about 930, about 935, about940, about 945, about 950 ng·hr/mL, or any other value or range ofvalues therein.

In one embodiment, the dosing frequency and dose amount of thecontrolled release formulation provides a nalbuphine AUC_((0-∞)) of fromabout 37 ng·hr/mL to about 910 ng·hr/mL. In another embodiment, thecontrolled release formulation provides a nalbuphine AUC_((0-∞)) of fromabout 200 ng·hr/mL to about 500 ng·hr/mL. In another embodiment, thecontrolled release formulation provides a nalbuphine AUC_((0-∞)) of fromabout 70 ng·hr/mL to about 210 ng·hr/mL. In yet another embodiment, thecontrolled release formulation provides a nalbuphine AUC_((0-∞)) of fromabout 50 ng·hr/mL to about 800 ng·hr/mL. In still another embodiment,the controlled release formulation provides a nalbuphine AUC_((0-∞)) offrom about 60 ng·hr/mL to about 720 ng·hr/mL. In still anotherembodiment, the controlled release formulation provides a nalbuphineAUC_((0-∞)) of from about 60 ng·hr/mL to about 80 ng·hr/mL.

In some embodiments, the dosing frequency and dose amount of thecontrolled release formulation provides a nalbuphine AUC_((0-∞)) of fromabout 142 ng·hr/mL to about 2640 ng·hr/mL, e.g., for subjects withuremic pruritus or renal impairment or from about 49 ng·hr/mL to about600 ng·hr/mL, e.g., for subjects without any renal impairment.

In other embodiments, the present formulations provide a nalbuphineAUC_((0-inf)) from about 1.392 (ng*hr/ml)/mg to about 3.43 (ng*hr/ml)/mg(e.g., about 1.4 (ng*hr/ml), about 1.5 (ng*hr/ml), about 1.6 (ng*hr/ml),about 1.7 (ng*hr/ml), about 1.8 (ng*hr/ml), about 1.9 (ng*hr/ml), about2.0 (ng*hr/ml), about 2.1 (ng*hr/ml), about 2.2 (ng*hr/ml), about 2.3(ng*hr/ml), about 2.4 (ng*hr/ml), about 2.5 (ng*hr/ml), about 2.6(ng*hr/ml), about 2.7 (ng*hr/ml), about 2.8 (ng*hr/ml), about 2.9(ng*hr/ml), about 3.0 (ng*hr/ml), about 3.1 (ng*hr/ml), about 3.2(ng*hr/ml), about 3.3 (ng*hr/ml), about 3.4 (ng*hr/ml), or any othervalue or range of values therein).

In some embodiments, the present formulations provide a nalbuphineAUC_((0-inf)) from about 20 (ng*hr/ml)/mg to about 500 (ng*hr/ml)/mg. Insome other embodiments, the present formulations provide a nalbuphineAUC_((0-inf)) from about 30 (ng*hr/ml)/mg to about 450 (ng*hr/ml)/mg. Inyet some other embodiments, the present formulations provide analbuphine AUC_((0-inf)) from about 30 (ng*hr/ml)/mg to about 150(ng*hr/ml)/mg.

In some other embodiments, the dosing frequency and dose amount of thecontrolled release formulation provides a nalbuphine AUC_(tau) of fromabout 40 ng·hr/mL to about 800 ng·hr/mL (50 ng·hr/mL, 60 ng·hr/mL, 70ng·hr/mL, 80 ng·hr/mL, 90 ng·hr/mL, 100 ng·hr/mL, 120 ng·hr/mL, 140ng·hr/mL, 160 ng·hr/mL, 180 ng·hr/mL, 200 ng·hr/mL, 300 ng·hr/mL, 400ng·hr/mL, 500 ng·hr/mL, 600 ng·hr/mL, 700 ng·hr/mL, 750 ng·hr/mL, or anyother value or range of values therein), e.g., for subjects with uremicpruritus or renal impairment or from about 30 ng·hr/mL to about 360ng·hr/mL (40 ng·hr/mL, 50 ng·hr/mL, 60 ng·hr/mL, 70 ng·hr/mL, 80ng·hr/mL, 90 ng·hr/mL, 100 ng·hr/mL, 120 ng·hr/mL, 140 ng·hr/mL, 160ng·hr/mL, 180 ng·hr/mL, 200 ng·hr/mL, 220 ng·hr/mL, 240 ng·hr/mL, 260ng·hr/mL, 280 ng·hr/mL, 300 ng·hr/mL, 320 ng·hr/mL, 360 ng·hr/mL or anyother value or range of values therein), e.g., for subjects without anyrenal impairment.

In yet some other embodiments, the dosing frequency and dose amount ofthe controlled release formulation provides a mean C_(max) of about 1.5ng/mL and AUC_((0-inf)) of about 20 hr·ng/mL at 30 mg BID, e.g., forsubjects with uremic pruritus or renal impairment. In yet some otherembodiments, the dosing frequency and dose amount of the controlledrelease formulation provides a mean C_(max) of about 120 ng/mL andAUC_((0-inf)) of about 2000 hr·ng/mL at 120 mg BID, e.g., for subjectswith uremic pruritus or renal impairment. In yet some other embodiments,the dosing frequency and dose amount of the controlled releaseformulation provides a mean C_(max) of about 195 ng/mL and AUC_((0-inf))of about 4100 hr·ng/mL at 180 mg BID, e.g., for subjects with uremicpruritus or renal impairment. In yet some other embodiments, the dosingfrequency and dose amount of the controlled release formulation providesa mean C_(max) of about 60 ng/mL and AUC_((0-inf)) of about 1600hr·ng/mL at 240 mg BID, e.g., for subjects with uremic pruritus or renalimpairment.

In some embodiments, the dosing frequency and dose amount of thecontrolled release formulation provides a mean C_(max) of about 1.5ng/mL and AUC_((0-inf)) of about 20 hr·ng/mL at 30 mg BID, e.g., forsubjects without any renal impairment. In some other embodiments, thedosing frequency and dose amount of the controlled release formulationprovides a mean C_(max) of about 22 ng/mL and AUC_((0-inf)) of about 300hr·ng/mL at 60 mg BID, e.g., for subjects without any renal impairment.In some embodiments, the dosing frequency and dose amount of thecontrolled release formulation provides a mean C_(max) of about 60 ng/mLand AUC_((0-inf)) of about 700 hr·ng/mL at 180 mg BID, e.g., forsubjects without any renal impairment.

In certain embodiments, the present methods can further compriseadministering a rescue dose comprising nalbuphine to providebreakthrough relief of pruritus. The rescue dose can comprise nalbuphinein an amount of from about 1 mg to about 60 mg (e.g., about 1 mg, about2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg,about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about45 mg, about 50 mg, about 55 mg, about 60 mg, or any other value orrange of values therein). In some embodiments, the rescue dose comprisesfrom about 3 mg to about 30 mg of nalbuphine. In other embodiments, therescue dose comprises from about 3 mg to about 45 mg of nalbuphine. Therescue dose can be administered parenterally, orally in an immediaterelease formulation, or as a buccal, sublingual, intranasal, or rectaldosage form. In some embodiments, the rescue dose is a tablet, capsule,a solution, a lozenge, or a suppository. In other embodiments, therescue dose can be administered via a bilayer tablet which includes arescue nalbuphine dose in an immediate release layer, and the tabletfurther comprises a nalbuphine dose in an extended release layer.

In some embodiments, the present methods employ a twice daily dosageregimen, and the first daily dose is less than the second daily dose.For example, in some embodiments, the second daily dose is from about 5mg to about 180 mg greater than the first daily dose (e.g., about 5 mggreater, about 10 mg greater, about 15 mg greater, about 20 mg greater,about 25 mg greater, about 30 mg greater, about 35 mg greater, about 40mg greater, about 45 mg greater, about 50 mg greater, about 55 mggreater, about 60 mg greater, about 65 mg greater, about 70 mg greater,about 75 mg greater, about 80 mg greater, about 85 mg greater, about 90mg greater, about 95 mg greater, about 100 mg greater, about 105 mggreater, about 110 mg greater, about 115 mg greater, about 120 mggreater, about 125 mg greater, about 130 mg greater, about 135 mggreater, about 140 mg greater, about 145 mg greater, about 150 mggreater, about 155 mg greater, about 160 mg greater, about 165 mggreater, about 170 mg greater, about 175 mg greater, about 180 mggreater, or any other value or range of values therein).

In some embodiments, the second daily dose of nalbuphine can be selectedas described above, and then titrated upward until the patientexperiences satisfactory relief from the pruritic condition. Titratingthe dose can include administering a baseline second daily dose, thenafter a period of observation at the baseline second daily dose value todetermine the efficacy and/or side effect severity, of the baselinesecond daily dose, increasing the second daily dose if the subject doesnot experience adequate symptom relief. The period of observation at thebaseline second daily dose before increasing the second daily dose canbe from about 1 day to about 21 days (e.g., about 1 day, about 2 days,about 3 days, about 4 days, about 5 days, about 6 days, about 7 days,about 8 days, about 9 days, about 10 days, about 11 days, about 12 days,about 13 days, about 14 days, about 15 days, about 16 days, about 17days, about 18 days, about 19 days, about 20 days, about 21 days). Thesecond daily dose can be titrated in increments ranging from about 5 mgto about 180 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg,about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg,about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg,about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg,about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg,about 180 mg, or any other value or range of values therein). The seconddaily dose can be titrated in one or more steps. The amount a dosage isstepped, where there are multiple titration steps, can be the same, orcan be different.

In some embodiments, the present methods employ a twice daily dosageregimen, and the first daily dose is greater than the second daily dose.For example, in some embodiments, the first daily dose is from about 5mg to about 180 mg greater than the second daily dose (e.g., about 5 mggreater, about 10 mg greater, about 15 mg greater, about 20 mg greater,about 25 mg greater, about 30 mg greater, about 35 mg greater, about 40mg greater, about 45 mg greater, about 50 mg greater, about 55 mggreater, about 60 mg greater, about 65 mg greater, about 70 mg greater,about 75 mg greater, about 80 mg greater, about 85 mg greater, about 90mg greater, about 95 mg greater, about 100 mg greater, about 105 mggreater, about 110 mg greater, about 115 mg greater, about 120 mggreater, about 125 mg greater, about 130 mg greater, about 135 mggreater, about 140 mg greater, about 145 mg greater, about 150 mggreater, about 155 mg greater, about 160 mg greater, about 165 mggreater, about 170 mg greater, about 175 mg greater, about 180 mggreater, or any other value or range of values therein).

In some embodiments, the first daily dose of nalbuphine can be selectedas described above, and then titrated upward until the patientexperiences satisfactory relief from the pruritic condition. Titratingthe dose can include administering a baseline first daily dose, thenafter a period of observation at the baseline first daily dose value todetermine the efficacy of the baseline first daily dose and/or sideeffect severity, increasing the first daily dose if the subject does notexperience adequate symptom relief. The period of observation at thebaseline first daily dose before increasing the first daily dose can befrom about 1 day to about 21 days (e.g., about 1 day, about 2 days,about 3 days, about 4 days, about 5 days, about 6 days, about 7 days,about 8 days, about 9 days, about 10 days, about 11 days, about 12 days,about 13 days, about 14 days, about 15 days, about 16 days, about 17days, about 18 days, about 19 days, about 20 days, about 21 days). Thefirst daily dose may be from about 5 mg to about 180 mg (e.g., about 5mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg,about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg,about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg,about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg,about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg,about 165 mg, about 170 mg, about 175 mg, about 180 mg, or any othervalue or range of values therein).

The titration dose can be in increments ranging from about 5 mg to about180 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180mg, or any other value or range of values therein). The first daily dosecan be titrated in one or more steps. The amount a dosage is stepped,where there are multiple titration steps, can be the same, or can bedifferent.

Accordingly, the total daily dose in a once daily dosing regimen with atitration dose, including baseline dose and one or more titration doses,may be from about 5 mg to about 180 mg (e.g., about 5 mg, about 10 mg,about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg,about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170mg, about 175 mg, about 180 mg, or any other value or range of valuestherein).

In one embodiment, the initial dose is about 15 mg to about 30 mg once aday for a day or two, then about 30 mg twice a day for 2 to 3 days andthen increase to about 60 mg or 120 mg twice a day, e.g., for subjectswith uremic pruritus or renal impairment or about 90 mg or 180 mg twicea day, e.g., for subjects without renal impairment.

In one embodiment, the present methods include treating pruritus in ahuman patient, comprising (a) orally administering to a human patientsuffering from pruritus an initial dosing regimen of nalbuphine in acontrolled release formulation containing about 15 mg, 30 mg or 60 mgnalbuphine on a once a day or twice-a-day basis; (b) determining theeffectiveness of the dosing regimen of nalbuphine in treating thepatient's pruritus after at least about 1, 2 or 3 days of treatment; and(c) adjusting the dose and/or dosing interval of the oral controlledrelease nalbuphine formulation based on the information obtained in step(b) in order to provide improved efficacy of treatment of said patient'spruritus.

In other embodiments, the initial dosing is about 15 mg, 30 mg, or 60 mgonce a day or twice a day and an effective dosing is obtained viatitration, e.g., based on a pre-determined schedule, e.g., about 15 mg,30 mg or 60 mg increment after about 2 or 3 days or based on a scheduledesigned by the physician treating the patient.

In some other embodiments, the maximum daily dose is about 75 mg, 150mg, 180 mg, or 240 mg once a day, or 240 mg, 360 mg, 480 mg, 600 mg, or720 mg twice a day. In one embodiment, the maximum daily dose is about240 mg once a day or 480 mg twice a day, e.g., for subjects with orwithout renal impairment.

In some embodiments, the effectiveness of a dosage regimen can bedetermined by evaluation via a Pruritis Visual Analog Scale (VAS) test.In one embodiment, the effectiveness of a dosage regimen can bedetermined by evaluation via a Numerical Rating Scale (NRS). In yet someother embodiments, the effectiveness of a dosage regimen can bedetermined by evaluation via a Numerical Rating Scale (NRS) inassociation with Medical Outcomes Study (MOS), Itch MOS Sleep scale,Hospital Anxiety and Depression Scale (HADS), Patient Assessed DiseaseSeverity Scale, or Skindex-10 or a combination thereof. In still anotherembodiment, the effectiveness of a dosage regimen can be determined byevaluation via a NRS independently or in association with Patient GlobalAssessment (PGA) via ItchApp, vPGA, Dermatology Life Quality Index(DLQI), Patient Benefit Index (PBI), MOS Sleep Scale, or HADS or acombination thereof. In still yet another embodiment, the effectivenessof a dosage regimen can be determined by evaluation via a NRSindependently or in association with Prurigo Activity Score (PAS),Nocturnal scratching using actigraphy, nerve fiber density and MOR/KORdensity.

In other embodiments, determining the effectiveness of the dose ofnalbuphine can include evaluation of the patient's pruritus symptomsusing an instrument selected from the group consisting of PruritisVisual Analog Scale (VAS) test, Brief Itching Inventory, Skindex-10,Itch MOS of sleep, Beck Depression Index, and Patient Categorization ofPruritus Disease Severity.

In some embodiments, a subject, e.g., a human or animal patient can betreated initially with a twice-daily dosing regimen, and then aftertitrating either the first daily dose, the second daily dose, or both toarrive at a total daily dose effective to treat the patient's pruritussymptoms, the dosage regimen can be changed to a once-daily dosage. Eachdose of the twice daily dosage can then be further titrated as describedhereinabove to provide a therapeutically effective once daily dosage ofnalbuphine. Thus, in some embodiments, the dosage regimen is atwice-daily dose, and each of the first and second doses can be titratedto achieve maximum therapeutic effect and/or minimal side effectseverity. Accordingly, in some embodiments each of the first and seconddoses in a twice-daily dosage regimen may be from about 5 mg to about240 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230mg, about 240 mg or any other value or range of values therein).

In some embodiments, each of the first and second daily doses in a twicedaily dosage regimen may be independently titrated in an amount of fromabout 5 mg to about 240 mg (e.g., about 5 mg, about 10 mg, about 15 mg,about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg,about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about175 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about220 mg, about 230 mg, about 240 mg or any other value or range of valuestherein). The first and second doses in a twice-daily dosage regimen maybe independently titrated in one or more steps. The amount a dosage isstepped, where there are multiple titration steps, can be the same, orcan be different.

Accordingly, the total daily dose in a twice daily dosing regimen,including baseline dose for each administration and one or moretitration doses for each administration independently, may be from about5 mg a day to about 480 mg a day (e.g., about 15 mg a day, about 20 mg aday, about 25 mg a day, about 30 mg a day, about 35 mg a day, about 40mg a day, about 45 mg a day, about 50 mg a day, about 55 mg a day, about60 mg a day, about 65 mg a day, about 70 mg a day, about 75 mg a day,about 80 mg a day, about 85 mg a day, about 90 mg a day, about 95 mg aday, about 100 mg a day, about 105 mg a day, about 110 mg a day, about115 mg a day, about 120 mg a day, about 125 mg a day, about 130 mg aday, about 135 mg a day, about 140 mg a day, about 145 mg a day, about150 mg a day, about 155 mg a day, about 160 mg a day, about 165 mg aday, about 170 mg a day, about 175 mg a day, about 180 mg a day, about185 mg a day, about 190 mg a day, about 195 mg a day, about 200 mg aday, about 205 mg a day, about 210 mg a day, about 215 mg a day, about220 mg a day, about 225 mg a day, about 230 mg a day, about 235 mg aday, about 240 mg a day, about 245 mg a day, about 250 mg a day, about255 mg a day, about 260 mg a day, about 265 mg a day, about 270 mg aday, about 275 mg a day, about 280 mg a day, about 285 mg a day, about290 mg a day, about 295 mg a day, about 300 mg a day, about 305 mg aday, about 310 mg a day, about 315 mg a day, about 320 mg a day, about325 mg a day, about 330 mg a day, about 335 mg a day, about 340 mg aday, about 345 mg a day, about 350 mg a day, about 355 mg a day, about360 mg a day, about 390 mg, about 420 mg, about 450 mg, about 480 mg orany other value or range of values therein).

In some embodiments, the present methods employ a thrice daily dosageregimen, and the first daily dose is less than the second and thirddaily doses. For example, in some embodiments, the second and thirddaily doses may each independently be from about 5 mg to about 240 mggreater than the first daily dose (e.g., about 5 mg greater, about 10 mggreater, about 15 mg greater, about 20 mg greater, about 25 mg greater,about 30 mg greater, about 35 mg greater, about 40 mg greater, about 45mg greater, about 50 mg greater, about 55 mg greater, about 60 mggreater, about 65 mg greater, about 70 mg greater, about 75 mg greater,about 80 mg greater, about 85 mg greater, about 90 mg greater, about 95mg greater, about 100 mg greater, about 105 mg greater, about 110 mggreater, about 115 mg greater, about 120 mg greater, about 125 mggreater, about 130 mg greater, about 135 mg greater, about 140 mggreater, about 145 mg greater, about 150 mg greater, about 155 mggreater, about 160 mg greater, about 165 mg greater, about 170 mggreater, about 175 mg greater, about 180 mg greater, 190 mg, 200 mg, 210mg, 220 mg, 230 mg, 240 mg or any other value or range of valuestherein).

In some embodiments, each of the first, second and third doses in athrice-daily dosing regimen of nalbuphine can be selected as describedabove, and then titrated upward until the patient experiencessatisfactory relief from the pruritic condition. Titrating the dose caninclude administering a baseline dose, then after a period ofobservation at the baseline dose value to determine the efficacy and/orside effect severity, of the baseline dose, increasing the dose if thesubject does not experience adequate symptom relief. The period ofobservation at the baseline for any of the first, second and third dosesindependently can be from about 1 day to about 21 days (e.g., about 1day, about 2 days, about 3 days, about 4 days, about 5 days, about 6days, about 7 days, about 8 days, about 9 days, about 10 days, about 11days, about 12 days, about 13 days, about 14 days, about 15 days, about16 days, about 17 days, about 18 days, about 19 days, about 20 days,about 21 days). The dose (e.g., any one of three doses in a thrice dailydosing regimen) can be titrated in increments ranging from about 5 mg toabout 180 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg,about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg,about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about180 mg, or any other value or range of values therein). The second dailydose can be titrated in one or more steps. The amount a dosage isstepped, where there are multiple titration steps, can be the same, orcan be different.

In other embodiments, the present methods employ a thrice daily dosageregimen, and the first daily dose is greater than the second and thirddaily doses. For example, in some embodiments, the first daily dose isfrom about 5 mg to about 240 mg greater than the second and third dailydoses (e.g., about 5 mg greater, about 10 mg greater, about 15 mggreater, about 20 mg greater, about 25 mg greater, about 30 mg greater,about 35 mg greater, about 40 mg greater, about 45 mg greater, about 50mg greater, about 55 mg greater, about 60 mg greater, about 65 mggreater, about 70 mg greater, about 75 mg greater, about 80 mg greater,about 85 mg greater, about 90 mg greater, about 95 mg greater, about 100mg greater, about 105 mg greater, about 110 mg greater, about 115 mggreater, about 120 mg greater, about 125 mg greater, about 130 mggreater, about 135 mg greater, about 140 mg greater, about 145 mggreater, about 150 mg greater, about 155 mg greater, about 160 mggreater, about 165 mg greater, about 170 mg greater, about 175 mggreater, about 180 mg greater, about 190 mg greater, about 200 mggreater, about 210 mg greater, about 220 mg greater, about 230 mggreater, about 240 mg greater, or any other value or range of valuestherein).

In some embodiments, the each of the first, second and third doses in athrice-daily dosing regimen can be selected as described above, and thentitrated upward until the patient experiences satisfactory relief fromthe pruritic condition. Titrating the dose can include administering abaseline dose, then after a period of observation at the baseline dosevalue to determine the efficacy of the baseline dose and/or side effectseverity, increasing the dose if the subject does not experienceadequate symptom relief. The baseline dose may be from about 5 mg toabout 240 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg,about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg,about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about230 mg, about 240 mg, or any other value or range of values therein).

The titration dose can be in increments ranging from about 5 mg to about240 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg,about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230mg, about 240 mg, or any other value or range of values therein). Eachof the first, second and third doses can be titrated in one or moresteps. The amount a dosage is stepped, where there are multipletitration steps, can be the same, or can be different. Accordingly, thetotal daily dose in a thrice daily dosing regimen with a titration dose,including baseline doses and one or more titration doses, may be fromabout 5 mg to about 480 mg (e.g., about 5 mg, about 10 mg, about 15 mg,about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg,about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about175 mg, about 180 mg, about 210 mg, about 240 mg, about 270 mg, about300 mg, about 330 mg, about 360 mg, about 390 mg, about 420 mg, about450 mg, about 480 mg, or any other value or range of values therein).

Accordingly, the total daily dose in a thrice daily dosing regimen,including baseline dose for each administration and one or moretitration doses for each administration independently, may be from about5 mg a day to about 480 mg a day (e.g., about 15 mg a day, about 20 mg aday, about 25 mg a day, about 30 mg a day, about 35 mg a day, about 40mg a day, about 45 mg a day, about 50 mg a day, about 55 mg a day, about60 mg a day, about 65 mg a day, about 70 mg a day, about 75 mg a day,about 80 mg a day, about 85 mg a day, about 90 mg a day, about 95 mg aday, about 100 mg a day, about 105 mg a day, about 110 mg a day, about115 mg a day, about 120 mg a day, about 125 mg a day, about 130 mg aday, about 135 mg a day, about 140 mg a day, about 145 mg a day, about150 mg a day, about 155 mg a day, about 160 mg a day, about 165 mg aday, about 170 mg a day, about 175 mg a day, about 180 mg a day, about185 mg a day, about 190 mg a day, about 195 mg a day, about 200 mg aday, about 205 mg a day, about 210 mg a day, about 215 mg a day, about220 mg a day, about 225 mg a day, about 230 mg a day, about 235 mg aday, about 240 mg a day, about 245 mg a day, about 250 mg a day, about255 mg a day, about 260 mg a day, about 265 mg a day, about 270 mg aday, about 275 mg a day, about 280 mg a day, about 285 mg a day, about290 mg a day, about 295 mg a day, about 300 mg a day, about 305 mg aday, about 310 mg a day, about 315 mg a day, about 320 mg a day, about325 mg a day, about 330 mg a day, about 335 mg a day, about 340 mg aday, about 345 mg a day, about 350 mg a day, about 355 mg a day, about360 mg a day, about 390 mg a day, about 420 mg a day, about 450 mg aday, about 480 mg a day, or any other value or range of valuestherein,).

In some embodiments, a subject, e.g., a human or animal patient can betreated initially with a thrice-daily dosing regimen, and then aftertitrating either the first daily dose, the second daily dose, and/or thethird daily to arrive at a total daily dose effective to treat thepatient's pruritus symptoms, the dosage regimen can be changed to eithera twice-daily dosage or a once-daily dosage. Each dose of thethrice-daily dosage can be further titrated as described hereinabove toarrive at a therapeutically effective once daily dosage of nalbuphine.

In still other embodiment, the second dose in a thrice-daily dosingregimen may be greater than the first and third doses. In still otherembodiments, the third daily dose may be greater than each of the firstand second doses. Furthermore, as described above, each of the first,second and third doses in a thrice-daily regimen may be titratedindependently of the other two doses, to arrive at a therapeuticallyefficacious dosing regimen.

In some embodiments, the single daily dosage can be administered in theevening or before bedtime. In other embodiments, the single daily dosagecan be administered in the morning. In some embodiments, the singledaily dose can be administered around midday (e.g., from about 11 am toabout 1 pm). In twice-daily dosing regimens, the two doses may beadministered in the morning and evening. In a thrice daily dosingregimen, the three doses may be administered with one dose given in themorning, one dose given at midday and one dose given in the evening.

In some embodiments, the present methods include treating pruritus in asubject, e.g., a human or animal patient, comprising administering to asubject, e.g., a human or animal patient suffering from pruritus aneffective amount of a medication consisting of a pharmaceutical compoundwhich is a μ-opioid receptor antagonist and a pharmaceutical compoundwhich is a κ-opioid receptor agonist, or pharmaceutically acceptablesalts or esters thereof. In certain embodiments, the pharmaceuticalcompound which is a μ-opioid receptor antagonist and the pharmaceuticalcompound which is a κ-opioid receptor agonist are the same. In someembodiments, the compound is nalbuphine or a pharmaceutically acceptablesalt or ester thereof.

In certain embodiments, the anti-pruritic agent is nalbuphine, and themetabolites include glucuronides (most likely on the phenol andcyclohexane rings), two hydroxylated nalbuphine metabolites (on thecyclobutane ring) and three ketones (hydroxylation of the cyclobutanering, followed by oxidation to a carbonyl). In some embodiments, thenalbuphine metabolites include nornalbuphine, 6-ketonalbuphine andnalbuphine 3-glucuronide. In some other embodiments, the nalbuphinemetabolites include triple hydroxylated nalbuphine, mono-hydroxylatednalbuphine, or mono-glucuronidated nalbuphine or a combination thereof.In certain embodiments, the one or more metabolites of the anti-pruritusagent do not have detectable anti-pruritus activity. In otherembodiments, one or more of the metabolites of the anti-pruritus agentexhibit anti-pruritus activity.

In embodiments wherein one or more metabolites of the anti-pruritusagent exhibit anti-pruritus activity, the dosing regimen of theanti-pruritus agent may be adjusted and/or titrated as describedhereinabove depending on the clearance rate of the one or moremetabolites exhibiting anti-pruritic activity. Such dosage adjustmentand/or titration of the dosage of the anti-pruritic agent can beperformed to prevent accumulation of either the anti-pruritic agentand/or one or more metabolites, which can also exhibit anti-pruriticactivity, to avoid toxicity effects in a patient treated with thepresent anti-pruritic agent.

In some embodiments, the anti-pruritus agent is completely metabolized(e.g., about 100% metabolized). In other embodiments, the anti-pruritusagent is not completely metabolized (e.g., less than about 100%metabolized). For example, in some embodiments, the anti-pruritus agentis about 100% metabolized, about 95% metabolized, about 90% metabolized,about 85% metabolized, about 80% metabolized, about 75% metabolized,about 70% metabolized, about 65% metabolized, about 60% metabolized,about 55% metabolized, about 50% metabolized, about 45% metabolized,about 40% metabolized, about 35% metabolized, about 25% metabolized,about 20% metabolized, about 15% metabolized, about 10% metabolized,about 5% metabolized, about 1% metabolized, or about 0% metabolized. Incertain embodiments, the amount of dialyzable anti-pruritus agent can bemeasured or monitored by the level of accumulation, e.g., blood plasmalevel of the anti-pruritus agent or one or more of its metabolites.

In some embodiments, the present methods can further comprise monitoringthe plasma concentration of either an anti-pruritic agent, or one ormore metabolites thereof. Such monitoring can be performed viameasurement of the concentration of the anti-pruritic agent, or one ormore metabolites thereof, in the blood of a patient via routine bloodtesting. Such testing can be conducted at suitable intervals todetermine the peak blood plasma concentration of the anti-pruriticagent, or one or more metabolites thereof. Titration of dosage asdescribed hereinabove can also be conducted via blood testing (inaddition to qualitative measures described hereinabove for determiningtherapeutic levels of pruritus relief) to maintain safe levels of theanti-pruritic agent, or one or more metabolites thereof, in the presentmethods. Once a clearance rate of the anti-pruritic agent, or one ormore metabolites thereof is established, an appropriate dosing regimencan be selected to provide target C_(max) and AUC_((0-∞)) ranges asdescribed herein above.

According to some embodiments of the present invention, administering ofnalbuphine or a pharmaceutically acceptable salt or ester thereofaccording to the methods of the present invention provides statisticallysignificant therapeutic effect. In one embodiment, the statisticallysignificant therapeutic effect is determined based on one or morestandards or criteria provided by one or more regulatory agencies in theUnited States, e.g., FDA or other countries. In another embodiments, thestatistically significant therapeutic effect is determined based onresults obtained from regulatory agency approved clinical trial set upand/or procedure.

In some embodiments, the statistically significant therapeutic effect isdetermined based on a patient population of at least 100, 200, 300, 400,500, 600, 700, 800, 900, 1000 or 2000. In some embodiments, thestatistically significant therapeutic effect is determined based on dataobtained from randomized and double blinded clinical trial set up. Insome embodiments, the statistically significant therapeutic effect isdetermined based on data with a p value of less than or equal to about0.05, 0.04, 0.03, 0.02 or 0.01. In some embodiments, the statisticallysignificant therapeutic effect is determined based on data with aconfidence interval greater than or equal to 95%, 96%, 97%, 98% or 99%.In some embodiments, the statistically significant therapeutic effect isdetermined on approval of Phase III clinical trial of the methodsprovided by the present invention, e.g., by FDA in the US.

In some embodiment, the statistically significant therapeutic effect isdetermined by a randomized double blind clinical trial of a patientpopulation of at least 300 or 350; treated with nalbuphine or apharmaceutically acceptable salt or ester thereof and optionally incombination with standard care. In some embodiment, the statisticallysignificant therapeutic effect is determined by a randomized clinicaltrial of a patient population of at least 300 or 350 and using NRS asprimary efficacy parameter and optionally in combination with any othercommonly accepted criteria for pruritus assessment.

In general, statistical analysis can include any suitable methodpermitted by a regulatory agency, e.g., FDA in the US or Europe or anyother country. In some embodiments, statistical analysis includesnon-stratified analysis, log-rank analysis, e.g., from Kaplan-Meier,Jacobson-Truax, Gulliken-Lord-Novick, Edwards-Nunnally, Hageman-Arrindeland Hierarchical Linear Modeling (HLM) and Cox regression analysis.

The following non-limiting examples illustrate various aspects of thepresent invention.

EXAMPLES Examples 1 to 3

Three sustained release delivery systems were prepared by dry blendingxanthan gum, locust bean gum, calcium sulfate dihydrate, and mannitol ina high speed mixed/granulator for 3 minutes. While runningchoppers/impellers, water was sprayed to the dry blended mixture, andgranulated for another 6 minutes. Then the granulation process wasstopped and the mixer/granulation bowl was scraped. While runningchoppers/impellers, the granulation was mixed for one more minute. Afterthe granulation was checked for consistency, while runningchoppers/impellers additional water was added to the granulation andgranulated for additional 3.5 minutes. The granulation was then dried toLOD (loss on drying) of less than about 4% by weight. The granulationwas then milled using screen #1521-0033. The relative quantities of theingredients are listed in Table 1.

TABLE 1 Sustained Release Delivery Example 1 Example 2 Example 3 SystemExcipient % % % Xanthan Gum, NF 8.0 12.0 20.0 Locust Bean Gum, FCC 12.018.0 30.0 Mannitol, USP 70.0 60.0 40.0 Calcium Sulfate Dihydrate, NF10.0 10.0 10.0 Sterile Water for Injection, USP¹ — — — Total 100.0 100.0100.0 ¹Sterile Water for Injection, USP is removed during processing

Examples 4 to 7

A series of tablets containing different amounts of gum were preparedusing the sustained release delivery system of Example 3. The quantitiesof ingredients per tablet are listed in Table 2.

TABLE 2 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Component Mg Mg mg mg Nalbuphine 60  60   60   60   HCI, USP Sustained 60¹  120¹   180¹   90¹  releasedelivery system Magnesium 0.5 1.8 1.2  0.75 stearate, NF Total Weight120.5  181.8  241.2  150.75  Active:Gum 1:0.5 1:1 1:1.5 1:0.75 ToolingSize   0.2812″   0.2812″   0.3125″   0.2812″ Hardness (Kp) 1.2 8.8 8.97.2 ¹Sustained release system of Example 3

The tablets were prepared by mixing nalbuphine with the sustainedrelease delivery system in a mixer. The magnesium stearate was passedthrough a #30 mesh screen sieve and then mixed with the dry blendcontaining nalbuphine and the sustained release delivery system. Thislubricated blend was compressed using the tooling as specified in Table2 to make tablets of the total weight indicated.

The tablets of Examples 4-7 were tested for in vitro % release rateaccording to USP Procedure Drug Release General Chapter <711>Dissolution, using apparatus USP Type III/250 mL. The test was performedat pH 6.8, 37° C./15 dpm (dips per minute) in 100 mM ammonium phosphatebuffer. The results are shown in Table 3.

TABLE 3 Dissolution Time Example 4 Example 5 Example 6 Example 7 (hours)pH 6.8 pH 6.8 pH 6.8 pH 6.8 0 0 0 0 0 1 29.3 23.8 19.5 25.0 2 41.8 35.129.4 35.9 4 59.2 51.7 45.0 53.0 6 72.9 65.6 56.4 67.1 8 84.2 77.8 65.379.6 12  98.1 92.9 81.0 93.9 Remnant 4.3 6.9 16.3 6.0 % Recovery 102.498.8 97.3 99.9

Examples 8 to 10

A series of tablets containing different amounts of gum and differentsustained release delivery systems were prepared using the sustainedrelease delivery systems of Examples 1 and 2. The quantities ofingredients per tablet are listed in Table 4.

TABLE 4 Ex. 8 Ex. 9 Ex. 10 Component mg Mg mg Nalbuphine 60 60 60 HCI,USP Sustained 225² 150³ 100³ release delivery system Magnesium    1.43  1.1   0.8 stearate Total weight  286.4  211.1  160.8 Active:Gum 1:0.751:0.75 1:0.5 Tooling Size     0.3125″     0.3125″     0.2812″ Hardness(Kp) 20 17 20 ²Sustained release delivery system of Example 1 ³Sustainedrelease delivery system of Example 2

The tablets were prepared by first mixing nalbuphine with the sustainedrelease delivery system in a mixer for Example 8 and in a high sheargranulator for Example 9 and 10. For Examples 9 and 10, the blend wasthen granulated with water until consistent granulation was achieved,followed by drying in a fluidized bed dryer for 30 minutes at 70° C. Thedried granules were then passed through a Fitzmill at 2500 rpm using1521-0050 screen. The magnesium stearate was passed through a #30 meshscreen sieve, and then mixed with the milled granules for Examples 9 and10 and with the dry blend for Example 8 for 5 minutes. The lubricatedblend was compressed using the tooling as specified in Table 4 to maketablets of the total weight indicated.

The tablets of Examples 8-10 were tested for in vitro % release rateaccording to USP Procedure Drug Release General Chapter <711>Dissolution, using apparatus USP Type III/250 mL. The test was performedin pH change, at 37° C./15 dpm. The pH change was as follows: pH 1.2 forthe first hour, pH 4.5 for the second hour, and pH 6.8 after the secondhour and through the duration of the test. The results are shown inTable 5.

TABLE 5 Dissolution Example 8 Example 9 Example 10 Time (hours) pHchange pH change pH change 0 0.0 0 0 1 19.4 18.8 22.5 2 36.4 39.7 45.3 459.0 66.3 73.2 6 72.5 82.6 89 8 79.4 89.8 95.9 12  82.1 92.3 100.1Remnant 0.1 0.1 0.8 % Recovery 82.2 92.4 100.9

Examples 11 to 16

To determine the effect of the amount of gum in combination withmicrocrystalline cellulose (Emococel 90M), six batches of tablets wereprepared using the sustained release delivery system of Example 3. Therange of Active: Gum ratios used in Examples 11-16 varied between 1:0.25and 1:0.5. Compositions of the tablets are shown in Table 6.

TABLE 6 Ex. 11 Ex. 12 Ex. 13 Ex. 14 Ex. 15 Ex. 16 Ingredient mg/tabmg/tab mg/tab mg/tab mg/tab mg/tab Sustained  30⁴  60⁴  60⁴  30⁴  60⁴ 60⁴ release delivery system Nalbuphine 60 60 60 60 60 60 HCl Micro- 3030 60 60 120  — crystalline Cellulose Magnesium   0.6   0.8   0.9   0.8  1.2   0.6 stearate Total Weight  120.6  150.8  180.9  150.8  241.2 120.6 (mg) Active:Gum 1:0.25 1:0.5 1:0.5 1:0.25 1:0.5 1:0.5 ToolingSize 0.2500″ 0.2812″ 0.2812″ 0.2812″ 0.3125″ 0.2500″ Hardness (Kp)  10.2 10 12 13 22   13.2 ⁴Sustained release delivery system of Example3

The tablets of Examples 11-15 were prepared by first sifting magnesiumstearate through #30 mesh screen sieve. Then blend nalbuphine with thesustained release delivery system, and magnesium stearate in a blenderfor 5 minutes. The lubricated blend was compressed using the tooling asspecified in Table 6 to make tablets of the total weight indicated.

The tablets of Example 16 were prepared by mixing nalbuphine in a highshear granulator with the sustained release delivery system. The blendwas then granulated with water until consistent granulation wasachieved. The granulation is then dried in a fluidized bed dryer for 40minutes at 70° C. The dried granules were then passed through a Fitzmillat 2500 rpm using 1521-0050 screen. The magnesium stearate was passedthrough a 430 mesh screen sieve and then mixed with the milled granulesfor 5 minutes. The lubricated blend was compressed using the tooling asspecified in Table 6 to make tablets of the total weight indicated.

The tablets of Examples 11-16 were tested for in vitro % release rateaccording to USP Procedure Drug Release General Chapter <711>Dissolution, using apparatus USP Type III/250 mL. The test was performedin pH change, at 37° C./15 dpm, as described above for Examples 8-10.The results are shown in Table 7.

TABLE 7 Dissolution time Ex. 11 Ex. 12 Ex. 13 Ex. 14 Ex. 15 Ex. 16(hours) pH change pH change pH change pH change pH change pH change 00.0 0.0 0.0 0.0 0.0 0.0 1 93.2 59.4 94.5 93.4 92.1 17.1 2 94.4 73.0 96.094.8 93.4 39.7 4 94.5 84.5 96.0 94.8 93.5 64.4 6 94.5 87.4 96.0 94.893.5 74.6 8 94.5 88.7 96.0 94.8 93.5 81.5 12  94.5 90.2 96.0 94.8 93.593.1 Remnant 0.0 1.2 0.0 0.0 0.0 7.0 % Recovery 94.5 91.5 96.0 94.8 93.5100.1

Examples 17 and 18

Two batches of bi-layer tablets were prepared using the sustainedrelease delivery system of Example 2 (Examples 17 and 18). In thebi-layer tablets, the first layer of the tablets was formulated toprovide relatively a slow sustained release; the second layer wasformulated to provide relatively fast (immediate) release. The in vitrodissolution profiles of the bi-layer tablets were compared to thedissolution profile of single layer tablets that were formulated toprovide a sustained release (Example 9). Compositions of the tablets areshown in Table 8.

TABLE 8 Example 17 Example 18 Example 9 Ingredient mg/tab mg/tab mg/tabExtended release layer (ER) Sustained release delivery 112.5⁵ 112.9⁵ 150system Nalbuphine HCI 45 45 60 Magnesium stearate 0.8 0.8 1.1 ER weight158.3 158.3 211.1 Immediate release layer (IR) Sustained releasedelivery 6.05 N/A system Nalbuphine HCI 15.0 N/A MicrocrystallineCellulose, 35.7 N/A NF (Emcocel 90 M) Croscarmellose Sodium, NF 3.0 N/A(Primellose ®) Magnesium stearate, NF 0.3 N/A IR Weight 60.0 N/A TotalWeight 218.3 218.3 211.1 Active:Gum 1:0.6 1:0.6 1:0.75 Tooling Size0.2812″ 0.2812″ 0.3125″ Hardness N/A N/A 17 ⁵Sustained release deliverysystem of Example 2

For the extended release layer, the nalbuphine was mixed with thesustained release delivery system in a high shear granulator for 3minutes. The mixture was granulated with water until consistentgranulation was achieved, then the wet mass was dried in a fluidized beddryer for 20 minutes at 70° C. The dried granules were then passedthrough a Fitzmill at 2500 rpm using 1521-0050 screen. For the immediaterelease layer, the nalbuphine was blended with the sustained releasedelivery system, microcrystalline cellulose (Emcocel® 90M), andcroscarmellose sodium, NF (Primellose®) in a V-Blender for 10 minutes.The magnesium stearate was passed through a #30 mesh screen sieve. Themilled granules of the slow release layer was mixed with the sievedmagnesium stearate in a V-blender for 5 minutes and the dry blend of theimmediate release layer was mixed with the sieved magnesium stearate ina V-blender for 5 minutes, separately. This lubricated blend of theextended release layer and the immediate release layer were thencompressed into bi-layer tablets using the tooling specified in Table 8,to make the tablets of the total weight indicated.

The tablets of Examples 17-18 were tested for in vitro % release rateaccording to USP Procedure Drug Release USP General Chapter <711>Dissolution, using apparatus USP Type III/250 mL. The test was performedin pH change as described above for Examples 8-10, at 37° C./15 dpm, asdescribed above for Examples 8-10. The results are shown in Table 9. Forpurposes of comparing the dissolution profiles of the bi-layer tabletswith a single-layer tablet, the dissolution data for Example 9 is alsoshown in Table 9.

TABLE 9 Dissolution Ex. 17 Ex. 18 Ex. 9 time (hours) pH change pH changepH change 0 0  0.0 0 1 44.5 42.6 18.0 2 62.8 62.7 39.7 4 83.1 84.3 66.36 92.3 92.3 82.6 8 94.0 93.7 89.8 12  94.0  93.9 - 92.3 Remnant 0.0 0 0.1 % Recovery 94.1 93.9 92.4

Examples 19 and 20

For a clinical study, one batch of bi-layer tablets and one batch ofsingle layer tablets were prepared using the sustained release deliverysystem of Example 2. The first layer of the tablets was formulated toprovide relatively a slow sustained release; the second layer wasformulated to provide relatively fast (immediate release). Compositionsof the tablets are shown in Table 10.

TABLE 10 Component Amount mg/tablet (%) Ingredient Example 19(F-2)Example 20(F-1) Extended release player (ER) Sustained Release Excipient(30%) 112.5⁶ 150.0⁶ Nalbuphine HCI 45.0 60.0 Magnesium stearate, NF 0.81.10 Sterile Water for Injection, USP • • • Mg/tablet weight (ERportion) 158.3 211.1 Immediate release layer (IR) Nalbuphine HCI 15.0Microcrystalline Cellulose, NF 41.7 Croscarmellose Sodium, NF 3.0Magnesium stearate, NF 0.3 Mg/tablet weight (IR portion) 60.0 TotalWeight (mg/tablet) 218.3 211.1 Type of tablet Bi-layer(ER/IR) Singlelayer (ER) Active to Gum Ratio 1:0.75 1:0.75 Tooling Size 0.3125 0.3125Hardness ~11 Kp ~11 Kp • Sterile Water for Injection, USP is removedduring process ⁶Sustained release delivery system of Example 2

For the extended release layer of Example 19 and 20, the nalbuphine wasmixed with the sustained release delivery system in a high sheargranulator (6-liter Diosna-Pharma Mixer 1/6) for 5 minutes with theimpeller speed at 300 rpm and the chopper off. After the mixer stopped,the bowl was scraped and sample was taken for LOD. While the impellerand the chopper are running at 300 rpm, the mixture was granulated withwater for 2 minutes. After the mixer stopped, the bowl was scraped.While impeller speed is running at 500 rpm and the chopper speed at 300rpm, the granulation was continued by mixing for an additional 1 minute.At the end of mixing the bowel was scraped. While the impeller andchopper were running at 300 rpm, additional of water (about 50.0 g) wasadded and granulated for 2 minutes in Example 19 and for 1 minute inExample 20. To achieve consistent granules, the granulation was mixedfor additional 3 minutes in Example 19 and 1 minute in Example 20, whilethe impeller and chopper were running at 500 and 300 rpm, respectively.Then the wet mass was dried in a Uni-Glatt fluid bed dryer for 30minutes at 70° C. The dried granules were then passed through aFitzmill, knives forward, with the speed of 2200-2700 rpm using1521-0033 screen. The magnesium stearate was passed through a #30 meshscreen sieve. The milled granules of the extended release layer forExample 19 and 20 were mixed separately with the sieved magnesiumstearate in a V-blender with a 4-quart stainless steel shell for 5minutes.

For Example 20, the lubricated blend of the extended release layer wascompressed into single layer tablets with the Piccola tablet press usingthe tooling specified in Table 11, to make the tablets of the totalweight indicated.

In the immediate release layer portion of Example 19, the nalbuphine wasblended with the microcrystalline cellulose (Emcocel 90M) in a P-K BlendMaster V-Blender for 5 minutes. To the mixture, croscarmellose sodium,NF (Primellose®) was added and mixed for 5 minutes. The magnesiumstearate was passed through a #30 mesh screen sieve. The milled granulesof the extended release layer portion of Example 19 was mixed with thesieved magnesium stearate in a V-blender with a 4-quart stainless steelshell for 5 minutes and the dry blend of the immediate release layerportion was mixed with the sieved magnesium stearate in a V-blender witha 4-quart stainless steel shell for 5 minutes, separately. Thislubricated blend of the extended release layer portion and the immediaterelease layer portion were then compressed into bi-layer tablets withthe Piccola tablet press using the tooling specified in Table 10, tomake the tablets of the total weight indicated.

The tablets of Examples 19-20 were tested for in vitro % release rateaccording to USP Procedure Drug Release USP General Chapter <711>Dissolution, using apparatus USP Type III/250 mL. The test was performedin pH 6.8, at 37° C./15 dpm. The results are shown in Table 11.

TABLE 11 Dissolution Time (h) Example 19(F-2) Example 20(F-1) 0 0 0 1 4726 3 69 51 4 77 61 6 88 76 8 95 86 12  99 96 Remnant 0 2 Recovery 99 98

These data demonstrate that the dissolution rate from the bi-layer(ER/IR) formulation (Example 19(F-2)) was about 21% and 16% faster thanthe rate from the single layer (ER) formulation (Example 20(F-1)) at 1and 4 hours time point, respectively.

Clinical Study

A Phase I, open label, five treatment arm, single dose escalation studyunder fasting conditions was conducted and pharmacokinetic data wereobtained with the following formulations: a) the sustained deliverysystem-nalbuphine 60 mg bi-layer tablet (IR/ER) (Example 19 (F-2)), b)the sustained delivery system-nalbuphine 60 mg single layer tablet (ER)(Example 20(F-1)), c) two tablets of the 60 mg single layer tablet (ER,120 mg total dose), d) three tablets of the 60 mg single layer tablet(ER, 180 mg total dose) and e) a dose of nalbuphine immediate release 60mg oral solution (control). Eleven healthy volunteers were initiallyenrolled with six subjects completing all five treatments. Thepharmacokinetic data are summarized below both as arithmetic andgeometric mean results. The mean blood level (“plasma”) concentration ofnalbuphine for each time point is shown in Table 16. A logarithmic graphof the mean nalbuphine plasma concentration versus time for eachformulation is shown in FIG. 1.

TABLE 12 Pharmacokinetic Parameters Arithmetic Mean Values Cmax •TmaxAUC(0-t) AUC(0-∞) Formulation ng/mL (h) (ng · h/mL) (ng · h/mL) 60 mg(F-2) 8.58 1.5 75.95 83.87 60 mg (F-1) 7.17 3.5 78.73 90.70 120 mg (F-1)12.87 6.0 154.63 170.75 180 mg (F-1) 15.59 8.0 200.63 213.22 60 mg oral13.75 1.0 61.85 68.50 solution (IR) •Median Tmax values reported

TABLE 13 Relative Bioavailability (based on dose normalized arithmeticmean values) Cmax AUC (0-t) AUC (0-∞) ratio ratio ratio 60 mg (F-2)/ER0.62 1.23 1.22 60 mg (F-1)/ER 0.52 1.27 1.32 120 mg (F-1)/ER 0.47 1.251.25 180 mg (F-1)/ER 0.38 1.08 1.04

TABLE 14 Pharmacokinetic Parameters Geometric Mean Values Cmax AUC(0-t)AUC(0-∞) Formulation ng/mL (ng · h/mL) (ng · h/mL) 60 mg (F-2) 7.5868.72 77.85 60 mg (F-1) 6.28 69.95 85.65 120 mg (F-1) 12.24 140.61158.62 180 mg (F-1) 13.67 175.73 189.32 60 mg oral 12.48 56.29 63.14solution (IR)

TABLE 15 Relative Bioavailability (based on dose normalized arithmeticmean values) Cmax AUC (0-t) AUC (0-∞) ratio ratio ratio 60 mg (F-2)/ER0.62 1.22 1.23 60 mg (F-1)/ER 0.50 1.24 1.36 120 mg (F-1)/ER 0.49 1.251.26 180 mg (F-1)/ER 0.37 1.04 1.00

TABLE 16 Nalbuphine Plasma Concentration Concentration (ng/mL) TimePoint 60 mg 60 mg 120 mg 180 mg (hrs) 60 mg IR (F-1) (F-2) (F-1) (F1) 00 0 0 0 0 0.25 10.57 1.83 0.79 1.01 1.00 0.5 14.81 4.69 1.71 2.94 3.55 113.53 7.57 3.33 6.51 7.87 1.5 11.20 7.42 3.63 8.81 10.59 2 9.77 6.895.88 9.41 11.40 3 6.58 6.18 4.96 9.04 11.90 4 4.65 5.36 4.77 8.20 10.716 3.29 5.31 6.18 10.45 14.01 8 1.76 4.00 4.76 8.55 10.59 12 1.67 2.833.32 6.77 9.20 16 1.01 1.87 2.24 4.27 5.14 20 0.76 1.13 1.51 2.96 3.2724 0.68 0.84 1.11 2.02 2.46 36  NT• 0.57 0.54 0.94 0.98 48 NT NT NT NT0.75 •Not tested

In general, the F-1 (Example 20) and F-2 (Example 19) formulations hadhigher AUCs (0-t and 0-∞) and lower Cmax values (for both arithmetic andgeometric mean values) compared to the immediate release oral solution.These differences were moderate for AUCs (0-t and 0-∞) and moderate tosignificant for Cmax and were based on dose-normalized comparisons ofthe F-1 and F-2 formulations with the immediate release oral solution.Minimal differences in AUCs (0-t and 0-∞) were seen between the F-1 andF-2 formulations at a comparative dose of 60 mg.

These data demonstrate that the oral bioavailability for the sustainedrelease nalbuphine formulations was greater than that of the immediaterelease control formulation. Specifically, the oral availability offormulation F-2 was 23% greater than that of the immediate release oralsolution, based on the geometric mean values for the area under theplasma concentration time curve. Similarly, the oral bioavailability ofFormulation F-1 was 36% greater than that of the immediate release oralsolution, based on the geometric mean values for the area under theplasma concentration time curve.

The C_(max) values for the sustained release formulations wereapproximately 60% of the C_(max) observed with the immediate releaseoral solution. These data suggest that the potential for adverse events(i.e., side effects) could be decreased with the sustained releaseformulation compared to immediate release formulations.

Median T_(max) values reported were 1.0, 1.5 and 3.5 hours for the oralsolution, F-2 and F-1 formulations, respectively. Longer T_(max) valueswere observed for the 2 higher doses of the F-1 formulation (6.0 and 8.0hours for the 120 and 180 mg doses, respectively).

Dose linearity was observed for all three doses of the F-1 formulation(60, 120 and 180 mg.

As shown in FIG. 1, the blood plasma concentration of nalbuphine for theextended release formulations increases quickly to one or more peaksshortly following administration, followed by a plateau region. Theduration of the plateau period varies based on the dose strength andtype of formulation, but is generally in the range from about 1.5 hoursto about 10 hours. In contrast, the blood plasma level for the immediaterelease formulation quickly maximizes, followed by an immediate decreasein nalbuphine concentration from time point to time point. Following theplateau period, there is a decrease in the nalbuphine blood plasmaconcentration from one time point to the next.

Example 21 Nalbuphine 60 mg Extended Release Tablets

The 60 mg extended release nalbuphine tablets of Example 21 wereprepared as follows: Nalbuphine HCl and TIMERx M30A were added to a highshear mixer and dry mixed at low speed. A granulating solution (waterfor injection or purified water) was then introduced to the mixer at lowspeed. The subsequent mixture was granulated at high speed and dried ina fluid bed processor. The dried granules were milled and sized via aconventional mill. The milled granulation was then transferred into adiffusion (tumble) mixer. Magnesium stearate was added to the diffusionmixer and blended. The final blend was compressed using a rotary tabletpress. The resulting tablets were then coated with the non-functionalcoating using a conventional coating pan.

TABLE 17 60 mg Extended Release Nalbuphine Tablet with Non-FunctionalCoating Ingredient mg/tablet Nalbuphine HCI 60.0 TIMERx M30A¹ 150.0(Mannitol) (90.0) (Locust bean gum) (27.0) (Xanthan Gum) (18.0) (Calciumsulfate dihydrate) (15.0) Magnesium stearate 1.1 Opadry II Purple 6.3Water for injection or QS Purified water Total: 217.4 ¹Sustained releaseexcipient of Example 2

The formulation of Example 21 is identical to the tablet formulation ofExamples 9 and 20, except with the addition of a non-functional coating.

Example 22 Nalbuphine 60 mg Extended Release Tablets

The 60 mg extended release nalbuphine tablets of Example 22 wereprepared as follows: Nalbuphine HCl and TIMERx M30A were added to a highshear mixer and dry mixed at low speed. A granulating solution (waterfor injection or purified water) was then introduced to the mixer at lowspeed. The subsequent mixture was granulated at high speed and dried ina fluid bed processor. The dried granules were milled and sized via aconventional mill. The milled granulation was then transferred into adiffusion (tumble) mixer. Hydroxypropyl cellulose was added to thediffusion mixer and blended. Thereafter, magnesium stearate was added tothe diffusion mixer and blended. The final blend was compressed using arotary tablet press. The resulting tablets were then coated with thenon-functional coating using a conventional coating pan.

TABLE 18 60 mg Extended Release Nalbuphine Tablet with Addition ofHydroxypropyl Cellulose and Reduction of TimeRx Excipient Ingredientmg/tablet Nalbuphine HCI 60.0 TIMERx M30A¹ 120.0 (Mannitol) (72.0)(Locust bean gum) (21.6) (Xanthan Gum) (14.4) (Calcium sulfatedihydrate) (12.0) Hydroxypropylcellulose 30.0 Magnesium stearate 1.6Water for injection or QS Purified water Total: 211.6 ¹Sustained releaseexcipient of Example 2

Examples 23-28

The nalbuphine tablets of Examples 23-28 were prepared as follows:Nalbuphine HCl, mannitol, xanthan gum, locust bean gum and calciumsulfate dihydrate were added to a high shear mixer and dried mix at lowspeed. A granulating solution (water for injection or purified water)was introduced into the mixer at low speed. The wet granulation wasgranulated at high speed and dried in a fluid bed processor. The driedgranules were milled and sized using a conventional mill. The milledgranulation was transferred into a diffusion (tumble) mixer.Hydroxypropylcellulose and, when applicable, fumaric acid (180 mgformulations only) were added to the diffusion mixer and blended.Thereafter, magnesium stearate was added to the diffusion mixer andblended. The final blend was compressed using a rotary tablet press.

TABLE 19 (Example 23) 30 mg Extended Release Nalbuphine TabletIngredient mg/tablet Nalbuphine HCI 30.0 Mannitol 108.0Hydroxypropylcellulose 35.0 Locust bean gum 32.4 Xanthan gum 21.6Calcium sulfate dehydrate 18.0 Magnesium stearate 1.9 Water forinjection or QS Purified water Total: 246.9

TABLE 20 (Example 24) 60 mg Extended Release Nalbuphine TabletIngredient mg/tablet Nalbuphine HCI 60.0 Mannitol 72.0Hydroxypropylcellulose 30.0 Locust bean gum 21.6 Xanthan gum 14.4Calcium sulfate dehydrate 12.0 Magnesium stearate 1.6 Water forinjection or QS Purified water Total: 211.6

TABLE 21 (Example 25) 120 mg Extended Release Nalbuphine TabletIngredient mg/tablet Nalbuphine HCI 120.0 Mannitol 144.0Hydroxypropylcellulose 60.0 Locust bean gum 43.2 Xanthan gum 28.8Calcium sulfate dehydrate 24.0 Magnesium stearate 3.2 Water forinjection or QS Purified water Total: 423.2

TABLE 22 (Example 26) 180 mg Extended Release Nalbuphine Tablet (release1 Ingredient mg/tablet Nalbuphine HCI 180.0 Mannitol 216.0Hydroxypropylcellulose 90.0 Locust bean gum 64.8 Xanthan gum 43.2Fumaric acid 25.0 Calcium sulfate dehydrate 36.0 Magnesium stearate 5.0Water for injection or QS Purified water Total: 660.0

TABLE 23 (Example 27) 180 mg Extended Release Nalbuphine Tablet (release2 Ingredient mg/tablet Nalbuphine HCI 180.0 Mannitol 162.0Hydroxypropylcellulose 60.0 Locust bean gum 48.6 Xanthan gum 32.4Fumaric acid 25.0 Calcium sulfate dehydrate 27.0 Magnesium stearate 4.0Water for injection or Purified water QS Total: 539.0

TABLE 24 (Example 28) 15 mg Extended Release Nalbuphine TabletIngredient mg/tablet Nalbuphine HCI 15.0 Mannitol 117.0Hydroxypropylcellulose 35.0 Locust bean gum 35.1 Xanthan gum 23.4Calcium sulfate dehydrate 19.5 Magnesium stearate 1.9 Water forinjection or Purified water QS Total: 246.9

Example 29

A Phase II, randomized, double-blind, single-dose, placebo-controlled,multi-center, parallel group study of the safety and efficacy of thenalbuphine bi-layer tablet formulation of Example 19 was conducted.Study subjects were randomized to active agent received either a single60 mg extended release dose of nalbuphine or a single 120 mg (2×60 mgtablets) dose of nalbuphine. Tables 25A-B provides a summary of theobserved pharmacokinetic parameters.

TABLE 25A (60 mg single dose) Cmax Tmax AUC Statistic (ng/mL) (hr) (ng ·hr/ml) N 65 65 65 Mean 8.1 4.5 75.2 SD 4.9 2.2 45.2 Minimum 3.0 0.5 23.6Median 6.6 6 65.3 Maximum 22.3 12 256.6 % CV 60.4% 48.5% 60.1% Geometricmean 6.9 3.9 64.8

TABLE 25B (120 mg single dose) Cmax Tmax AUC Statistic (ng/mL) (hr) (ng· hr/ml) N 66 66 66 Mean 16.4 4.3 149.2 SD 10.6 2.7 77.0 Minimum 4.6 0.533.2 Median 13.2 3 128.3 Maximum 77.4 12 450.2 % CV 64.9% 63.8% 51.6%Geometric mean 14.1 3.4 133.1

Example 30

A Phase I, randomized single dose, four period cross-over study toevaluate the effect of food on two nalbuphine extended release tabletformulations (bi-layer formulation of Example 19 and extended releaseformulation of Example 20) administered orally to healthy subjects underfed and fasted conditions was conducted. The total single doseadministered to each study subject was 120 mg (2×60 mg tablets). Table25 provides a summary of the observed pharmacokinetic parameters.

TABLE 26 C_(max) T_(max) AUC_((0-last)) AUC_((0-∞)) Treatment Statistics(ng/mL) (hr) (ng · hr/mL) (ng · hr/mL) Formula of N 9 9 9 9 Example 20Mean 14.1 — 170 183 120 mg Fast SD 6.23 — 59.7 62.9 Min 4.57 1.50 56.761.6 Median 15.1 6.00 179 195 Max 23.6 12.00 245 256 Formula of N 9 9 99 Example 20 Mean 22.4 — 201 211 120 mg Fed SD 12.7 — 67.2 68.3 Min 8.773.00 70.2 73.9 Median 21.0 6.00 219 227 Max 48.6 10.00 295 307 Formulaof N 9 9 9 9 Example 19 Mean 18.5 — 160 170 120 mg Fast SD 7.40 — 55.654.7 Min 6.33 1.00 81.5 87.7 Median 18.6 2.00 178 186 Max 28.7 6.00 239250 Formula of N 9 9 9 9 Example 19 Mean 28.0 — 204 214 120 mg Fed SD16.6 — 68.6 71.0 Min 11.0 2.00 98.2 111 Median 24.0 6.00 227 237 Max63.7 6.00 279 295

Example 31

A Phase I, randomized, single dose, four period, cross-over study toevaluate the intra-subject variability of two nalbuphine extendedrelease formulations (bi-layer formulation of Example 19 [ERF-2] andextended release formulation of Example 20 [ERF-1]) administered orallyto healthy subjects under fasted conditions was conducted. The totalsingle dose administered to each study subject was 120 mg (2×60 mgtablets). Table 27 provides a summary of the observed pharmacokineticparameters.

TABLE 27 C_(max) T_(max) AUC_((0-last)) AUC_((0-∞)) Treatment Statistics(ng/mL) (hr) (ng · hr/mL) (ng · hr/mL) ERF-1 (A1) N 7 7 7 7 Mean 11.3 —139 162 SD 7.17 — 75.0 78.8 Minimum 3.08 2.00 39.0 47.0 Median 12.1 6.00157 173 Maximum 20.5 12.00 257 279 ERF-1 (A2) N 7 7 7 6 Mean 13.4 — 152167 SD 8.81 — 73.5 80.9 Minimum 3.70 1.50 44.7 57.3 Median 12.3 6.00 128156 Maximum 30.2 8.00 252 263 ERF-2 (C1) N 7 7 7 6 Mean 14.2 — 148 170SD 8.87 — 78.3 78.2 Minimum 4.41 1.50 39.7 51.5 Median 8.57 6.00 123 176Maximum 26.6 8.00 259 265 ERF-2 (C2) N 7 7 7 6 Mean 12.5 — 137 155 SD8.02 — 77.5 78.9 Minimum 4.88 1.00 44.6 49.8 Median 9.17 2.00 142 161Maximum 26.3 10.00 270 277

Example 32

A phase I, randomized, single-blind, placebo-controlled, multipleascending dose tolerance trial of nalbuphine extended release tablets(of Example 21) in healthy adult subjects in the fasted state. Table 28and 29 provides a summary of the observed pharmacokinetic parameters.

TABLE 28 Single Dose Administration Pharmacokinetic Data 60 mg 120 mg180 mg 180 mg Parameter Statistics Period 1 Period 2 Period 3 Period 4Cmax N 3 5 3 5 (ng/mL) Mean 7.920 15.574 27.800 23.420 SD 1.4722 8.40709.9000 10.6302 Min 7.360 14.900 27.800 21.600 Median 6.81 5.47 17.9010.30 Max 9.59 27.80 37.70 39.80 Tmax (hr) N 3 5 3 5 Mean 5.67 3.60 5.673.00 SD 1.155 2.074 0.577 2.000 Min 5.00 4.00 6.00 3.00 Median 5.0 1.05.0 1.0 Max 7.0 6.0 6.0 5.0

TABLE 29 Multiple Doses Pharmacokinetic Data 60 mg 120 mg 180 mg 180 mgTreatment Statistics Period 1 Period 2 Period 3 Period 4 Cmax, ss N 3 53 5 (ng/mL) Mean 12.10 18.76 32.17 29.58 SD 1.217 1.806 8.810 11.107Median 11.50 19.00 29.10 27.40 Min 11.3 15.9 25.3 18.4 Max 13.5 20.642.1 46.7 Tmax, ss (hr) N 3 5 3 5 Mean 5.00 3.40 4.33 5.60 SD 1.0002.074 3.215 0.894 Median 5.00 3.00 3.00 5.00 Min 4.0 1.0 2.0 5.0 Max 6.06.0 8.0 7.0 Cmin, ss N 3 5 3 5 (ng/mL) Mean 3.263 5.974 12.067 7.232 SD0.7966 0.9232 1.6653 2.1101 Median 3.450 6.300 12.600 7.440 Min 2.394.85 10.20 4.84 Max 3.95 7.08 13.40 10.20

Example 33

A phase I, randomized, single dose, five-period cross-over study inhealthy subjects to evaluate the intra-subject variability of analbuphine extended release tablet formulation (of Example 22). Table 30provides a summary of the observed pharmacokinetic parameters.

TABLE 30 120 mg 120 mg (Fast) (Fed) Treatment Treatment TreatmentTreatment Oral Solution Oral Solution Parameter Statistics A1 A2 A BTreatment C Treatment D Cmax N 12 12 12 12 12 12 (ng/mL) Mean 12.49812.903 12.700 18.549 18.503 16.863 SD 7.1308 5.4062 5.7697 10.65607.8579 6.7619 Median 12.100 13.300 11.370 15.950 17.100 14.950 Min 4.033.83 3.93 5.79 8.53 8.62 Max 32.30 20.30 26.30 41.90 36.30 31.40 Tmax(hr) N 12 12 12 12 12 12 Mean 5.250 5.167 5.208 4.625 0.750 2.817 SD3.4411 2.6572 2.3400 2.0352 0.3371 0.8055 Median 3.500 6.000 5.750 6.0000.500 1.900 Min 2.00 1.00 2.00 1.50 0.50 1.00 Max 12.00 8.00 10.00 6.001.50 4.00 AUC (0-last) N 12 12 12 12 12 12 (ng · hr/mL) Mean 159.450154.391 156.921 169.723 83.793 103.154 SD 60.2859 59.9296 54.763570.0775 24.1551 27.2275 Median 155.720 151.944 158.828 168.859 84.097101.217 Min 56.97 54.32 55.65 56.76 51.24 63.89 Max 260.41 274.17 267.29282.63 143.74 147.43 AUC (0-∞) N 8 8 8 8 8 8 (ng · hr/mL) Mean 160.790161.532 161.161 170.590 85.926 103.053 SD 61.1655 54.6973 51.863869.3711 13.6623 29.5312 Median 152.985 166.487 167.257 162.708 90.05696.558 Min 64.80 63.01 63.91 66.16 63.66 70.24 Max 238.44 258.27 213.18272.16 104.20 151.97

Example 34

A phase I, open-label, single dose, five-period cross-over study todetermine the dose proportionality of 30, 60 120 and 180 mg nalbuphineextended release tablet formulations (of Examples 24-28). Table 31A-Eprovides a summary of the observed pharmacokinetic parameters for the 60mg, 120 mg and 180 mg formulations of Examples 25, 26, 27 and 28,respectively.

TABLE 31A C_(max) AUC_(last) AUC_(INF) Treatment T_(max)(hr) (ng/mL) (hr· ng/mL) (hr · ng/mL) Description Parameter N = 22 N = 22 N = 22 N = 1930 mg Mean 4.159 4.130 42.988 54.993 nalbuphine SD 1.996 2.338 20.13520.681 HCl ER Min 1.50 1.95 21.26 27.35 tablet Median 3.00 3.82 39.9953.13 Max 8.00 12.70 110.41 117.08

TABLE 31B C_(max) AUC_(last) AUC_(INF) Treatment T_(max)(hr) (ng/mL) (hr· ng/mL) (hr · ng/mL) Description Parameter N = 24 N = 24 N = 24 N = 2360 mg Mean 7.417 7.750 94.496 108.798 nalbuphine SD 2.962 6.034 40.00138.737 HCl ER Min 3.00 2.84 37.56 50.73 tablet Median 6.00 6.07 89.31103.12 Max 12.00 29.90 186.60 196.41

TABLE 31C C_(max) AUC_(last) AUC_(INF) Treatment T_(max)(hr) (ng/mL) (hr· ng/mL) (hr · ng/mL) Description Parameter N = 19 N = 19 N = 19 N = 18120 mg Mean 6.316 13.265 192.434 208.312 nalbuphine SD 2.709 6.45882.867 90.778 HCl ER Min 1.00 6.54 81.41 105.82 tablet Median 6.00 12.80197.01 205.96 Max 12.00 34.80 463.17 503.93

TABLE 31D C_(max) AUC_(last) AUC_(INF) Treatment T_(max)(hr) (ng/mL) (hr· ng/mL) (hr · ng/mL) Description Parameter N = 15 N = 15 N = 15 N = 15180 mg Mean 7.600 21.559 297.460 327.842 nalbuphine SD 3.043 23.526154.701 164.674 HCl ER Min 2.00 5.89 138.35 148.67 tablet Median 6.0016.30 274.64 288.86 (release 1) Max 12.00 102.00 722.79 760.86

TABLE 31E C_(max) AUC_(last) AUC_(INF) Treatment T_(max)(hr) (ng/mL) (hr· ng/mL) (hr · ng/mL) Description Parameter N = 19 N = 19 N = 19 N = 18180 mg Mean 8.000 19.182 318.759 339.507 nalbuphine SD 4.604 11.007167.371 117.176 HCl ER Min 1.00 8.25 151.52 156.52 tablet Median 6.0017.60 280.56 291.71 (release 2) Max 16.00 56.40 877.38 909.86

Example 35

The tablet of Example 28 was tested for % release according to USPProcedure Drug Release General Chapter <711> Dissolution, usingapparatus USP Type 111/250 mL. The test was performed at pH 6.8 and pH6.8, 37° C./15 dpm (dips per minute) in 100 mM ammonium phosphatebuffer. The results are shown in Table 32.

TABLE 32 Dissolution Time pH 4.5 pH 6.8 (hours) (% dissolution) (%dissolution) 0 0 0 1 30 41 3 58 64 4 68 71 6 81 84 8 89 92 12 97 101

Example 36

The tablet of Example 23 was coated with a non-functional coat and wastested in a clinical trial in renally impaired patients on hemodialysisand healthy subjects with normal kidney function and pK data werecollected following multiple ascending increasing doses.

TABLE 33 Nalbuphine HCl ER Tablets, 30 mg Composition Component Tablet(mg/tablet) Nalbuphine HCl 30.0 Mannitol 108.0 Hydroxypropylcellulose35.0 Locust bean gum 32.4 Xanthan gum 21.6 Calcium sulfate dihydrate18.0 Magnesium stearate¹ 1.9 Opadry II White 7.4 Sterile water forirrigation² QS 254.3

TABLE 34 Summary of PK Parameters following multiple ascending oraldoses of nalbuphine HCl ER tablets in hemodialysis (HD) patients andhealthy subjects (TREVI Clinical Study TR01) HD Patients HealthySubjects 30 mg 30 mg 60 mg 120 mg 180 mg 240 mg 30 mg 30 mg 60 mg 120 mg180 mg Descriptive QD BID BID BID BID BID QD BID BID BID BID ParameterStatistics (Day 1) (Day 4) (Day 6) (Day 9) (Day 13) (Day 15) (Day 1)(Day 4) (Day 6) (Day 9) (Day 13) AUCinf n 4 . . . 4 2 7 . . . 8(h*ng/mL) Mean 142.5 . . . 2635.38 1524.3 49.53 . . . 588.4 SD 33.28 . .. 2038.01 121.38 30.04 . . . 214.08 CV % 23.4 . . . 77.3 8 60.7 . . .36.4 Minimum 107.51 . . . 299.8 1438.48 17.01 . . . 211.06 Maximum 177 .. . 4543.71 1610.13 84.27 . . . 886.68 AUCtau n 15 14 10 10 9 3 9 9 9 98 (h*ng/mL) Mean 43.2 117.97 221.68 621.79 760.87 769.99 31.53 50.88106.11 240.37 351.15 SD 24.97 76.41 145.04 415.94 538.28 509.88 16.9327.54 50.49 93.68 118.21 CV % 57.8 64.8 65.4 66.9 70.7 66.2 53.7 54.147.6 39 33.7 Minimum 2.58 15.08 24.1 78.75 130.53 420.03 13.37 18.5134.42 122.53 139.51 Maximum 95.79 274.33 509.9 1233.92 1689.9 1355 57.0696.94 192.34 369.78 523.25 Cmax n 15 14 10 10 9 4 9 9 9 9 8 (ng/mL) Mean6.28 13.44 24.78 70.33 82.78 61.42 5.2 6.45 13.46 28 44.21 SD 3.36 8.3117.38 48.81 55.81 56.9 2.78 3.58 6.43 11.49 14.54 CV % 53.5 61.8 70.169.4 67.4 92.6 53.5 55.5 47.8 41 32.9 Minimum 0.65 1.65 2.63 9 14.7 4.282.56 2.53 4.9 17.1 25.2 Maximum 12.5 29.9 62.5 155 188 140 9.3 12.9 24.146.9 68.6 T½ n 4 . . . 4 2 7 . . . 8 (h) Mean 10.49 . . . 14.23 20.326.81 . . . 8.58 SD 2.22 . . . 3.24 0.41 2.79 . . . 2.05 CV % 21.1 . . .22.7 2 41 . . . 23.9 Minimum 8.1 . . . 10.02 20.03 3.92 . . . 4.84Maximum 13.46 . . . 17.77 20.61 11.64 . . . 11.88 Tmax n 15 14 10 10 9 49 9 9 9 8 (h) Minimum 1 0 0 3 2 0 2 2 2 3 2 Median 5 4 5 6 5 6.03 3 2 35 4 Maximum 18 9 9 9 7.1 12 5 6 6 9 6

TABLE 35 Trough (or Cmin) nalbuphine concentrations (ng/mL) as afunction of dose and dosing day in hemodialysis patients and healthysubjects (Clinical Study TR01) HD Subjects Healthy Subjects Descriptive30 mg 30 mg 60 mg 60 mg 120 mg 120 mg 180 mg 240 mg 30 mg 60 mg 120 mg180 mg Timepoint Statistics (Day 2) (Day 3) (Day 5) (Day 6) (Day 8) (Day10) (Day 11) (Day 13) (Day 2) (Day 5) (Day 8) (Day 11) PRE AM n 15 4 144 14 4 13 4 9 9 9 8 DOSE Mean 2.06 6 12.6 11.46 22.2 35.75 38.94 36.030.43 5.29 11.3 20.4 SD 1.34 4.3 8.75 7.13 14.47 26.81 28.12 20.1 0.542.96 4.71 11.71 CV % 65 71.6 69.4 62.3 65.2 75 72.2 55.8 125.4 56 41.757.4 Minimum 0 2.63 2.06 7.34 3.12 16.1 5.87 23.4 0 1.6 3.89 6.51Maximum 4.86 12.1 31.2 22.1 43 75.3 94.7 65.9 1.31 9.2 17.2 42.6 PRE PMn 15 4 14 4 14 4 12 4 9 9 9 8 DOSE Mean 5.25 5.57 11.86 10.92 26.7321.63 50.82 41.85 2.14 5.89 11.59 18.18 SD 2.78 2.2 8.15 5.88 17.03 6.637.16 22.08 1.06 2.56 4.97 6.05 CV % 53 39.5 68.7 53.8 63.7 30.5 73.152.8 49.6 43.6 42.9 33.3 Minimum 0.752 3.48 1.03 6.18 2.2 16.1 5.31 28.20.868 2.07 4.67 7.37 Maximum 10.1 8.63 25.4 19.5 61.2 29.4 109 74.5 3.659.35 18.7 27.3

The embodiments described herein and illustrated by the foregoingexamples should be understood to be illustrative of the presentinvention, and should not be construed as limiting. On the contrary, thepresent disclosure embraces alternatives and equivalents thereof, asembodied by the appended claims. Each reference disclosed herein isincorporated by reference herein in its entirety.

What is claimed is:
 1. A method of treating pruritus comprisingadministering an effective amount of an anti-pruritus agent to an animalin need of such treatment, wherein the anti-pruritus agent is nalbuphineor a pharmaceutically acceptable salt or ester thereof.
 2. The method ofclaim 1, wherein said animal is suffering from a pruritic condition, andsaid pruritic condition comprises atopic dermatitis, nervous dermatitis,contact dermatitis, seborrheic dermatitis, autosensitization dermatitis,caterpillar dermatitis, asteatosis, senile pruritus cutaneous, insectsting, photosensitive dermatosis, urticaria, prurigo, herpes, impetigo,eczema, tinea, lichen, psoriasis, scabies and acne vulgaris, or visceraldiseases complicated with pruritus.
 3. The method of claim 2, whereinsaid visceral diseases complicated with pruritus comprise malignanttumors, diabetes mellitus, hepatic diseases, renal failure or pregnancy.4. The method of claim 1, wherein said animal is suffering from a skinchange comprising pruritus secondary to inflamed skin, pruritus arisingfrom conditions of non-diseased skin, pruritus associated with chronicsecondary scratch, or skin lesions resulting from an underlying medicalcondition.
 5. The method of claim 4, wherein said underlying medicalcondition has an origin comprising dermatologic origin, systemic diseaseorigin, neurologic origin, psychogenic origin, or mixed origin.
 6. Themethod of claim 1, wherein said animal has uremic pruritus or prurigonodularis.
 7. The method of claim 1, wherein the anti-pruritus agent isadministered at an initial oral dose of from about 15 mg to about 30 mgtwice a day and then titrated to an effective dose.
 8. The method ofclaim 1, wherein the anti-pruritus agent is administered at an initialdose of from about 15 mg to about 30 mg once a day and then titrated toan effective dose.
 9. The method of claim 1, wherein the anti-pruritusagent is administered at an initial dose of from about 15 mg to about 30mg twice a day or once a day for about 2-3 days and then titrated to aneffective dose at about 15 mg to about 30 mg increment.
 10. The methodof claim 1, wherein the maximum dose of the anti-pruritus agent is about480 mg when said agent is administered to an animal twice a day or about240 mg when said agent is administered to an animal once a day.
 11. Themethod of claim 1, wherein the anti-pruritus agent is administered withan AM dosage and a PM dosage and wherein the PM dosage is higher thanthe AM dosage, or vice versa.
 12. The method of claim 1, wherein theanti-pruritus agent is administered at a dose of about 60 mg or about120 mg twice a day to an animal with renal impairment or about 90 mg orabout 180 mg twice a day to an animal without a renal impairmentcondition.
 13. The method of claim 1, wherein the anti-pruritus agent isin an extended release oral dosage form and the administration providesin the animal a mean C_(max) of from about 1 ng/mL to about 90 ng/mL,from about 5 ng/mL to about 85 ng/mL, from about 5 ng/ml to about 45ng/ml, from about 25 ng/mL to about 72 ng/mL, or from about 13 ng/mL toabout 28 ng/mL.
 14. The method of claim 1, wherein the anti-pruritusagent is in an extended release oral dosage form and the administrationprovides in the animal an AUC_((0-∞)) of from about 40 ng·hr/mL to about3000 ng·hr/mL, 40 ng·hr/mL to about 800 ng·hr/mL or 30 ng·hr/mL to about360 ng·hr/mL.
 15. The method of claim 1, wherein one or more of themetabolites of the anti-pruritus agent do not have detectableanti-pruritus activity.
 16. The method of claim 1, wherein theanti-pruritus agent is not administered in combination with a secondanti-pruritus agent.
 17. The method of claim 1, wherein theanti-pruritus agent is in an extended release oral dosage form.
 18. Themethod of claim 17, wherein the administration provides in the animal apK release profile with the characteristics of a) a mean C_(max) fromabout 1.5 ng/mL to about 195 ng/mL, and b) AUC_((0-∞)) from about 20ng·hr/mL to about 4100 ng·hr/mL.
 19. The method of claim 17, wherein theadministration provides in the animal a pK release profile with thecharacteristics of a) a mean C_(max) from about 1.5 ng/mL to about 60ng/mL, and b) AUC_((0-∞)) from about 20 ng·hr/mL to about 700 ng·hr/mL.20. The method of claim 17, wherein the anti-pruritus agent isadministered in a formulation comprising nalbuphine hydrochloride,mannitol, hydroxypropyl cellulose, locust bean gum, xanthan gum, calciumsulfate dihydrate and magnesium stearate.